Morpholine derivatives

ABSTRACT

Provided is a compound capable of inhibiting production or secretion of β amyloid protein. 
 
A compound represented by the following formula (1):  
                 
 
(wherein, R 1  represents a heterocyclic group which may have a substituent, R 2  represents a cyclic hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, R 3  represents a cyclic hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, R 4  represents a hydrogen atom or a C 1-6  alkyl group, and X represents —S—, —SO— or —SO 2 —); an N-oxide or S-oxide thereof; a salt thereof; or a solvate thereof; and a medicament containing any of them.

TECHNICAL FIELD

The present invention relates to novel compounds having an inhibitoryactivity against production or secretion of β-amyloid protein; and amedicament to treat various diseases caused by abnormal production orsecretion of β-amyloid protein such as Alzheimer disease, Down syndromeand the other diseases associated with amyloid deposition.

BACKGROUND ART

Alzheimer disease is a neurodegenerative disease having pathologicalfeatures such as degeneration or loss of nerve cells, formation ofsenile plaques and neurofibrillary tangles. Alzheimer disease causessymptoms of dementia such as gradual loss of memory, recognition,thinking, judgment or the like, and it eventually leads to death. Noeffective method for treating or preventing this disease has hithertobeen known.

The main protein constituting a senile plaque deposited in the brain isβ-amyloid protein (amyloid β protein, Aβ) which is composed of from 39to 43 amino acids. β-Amyloid protein exhibits cytotoxicity, which ispresumed to induce Alzheimer disease (Non-patent Document 1). β-Amyloidprotein secreted from cells is a polypeptide composed mainly of 40 or 42amino acids and particularly, that composed of 42 amino acids is knownto deposit in the brain quickly because of strong aggregation propertyand in addition, have strong cytotoxicity (Non-patent Document 2).Amyloid protein is produced ubiquitously in vivo, but its functionremains unknown.

β-Amyloid protein is produced by processing of an amyloid precursorprotein (APP) which is a membrane protein. Mutation of an APP gene isobserved from patients suffering from familial Alzheimer disease. Anincrease in the production or secretion amount of β-amyloid protein isknown to occur in the cells having this mutated APP gene introducedtherein. This suggests that a medicament inhibiting the production orsecretion of β-amyloid protein is effective for the prevention ortreatment of Alzheimer disease.

In the processing step of an amyloid precursor protein to produceβ-amyloid protein, BACE (β-site APP Cleaving Enzyme) (Non-patentDocument 3) or Asp1 (Non-patent Document 4), each an aspartic protease,is reported as a β secretase for cleaving the N terminal of β-amyloidprotein. It is suggested strongly that γ-secretase which cleaves theC-terminal region is partially composed of presenilin (Non-patentDocument 5). Although inhibitors of β-secretase and γ-secretase havebeen reported (Non-patent document 6), most of them are peptide likecompounds.

In Patent document 1, SMITH, et al., disclose compounds having asulfonamide skeleton and capable of controlling production of β-amyloidprotein. In Patent Document 2, BELANGER, et al., disclose compoundshaving a bicycloalkylsulfonamide skeleton and inhibiting γ-secretase.Also in Patent Documents 3, 4 and 5, diarylsulfone compounds inhibitingγ-secretase are disclosed. In Patent Document 6, thionaphthalenederivatives inhibiting aggregation of amyloid protein are disclosed.

Non-patent Document 1: Science, 259, 514(1993)

Non-patent Document 2: Journal of Biological Chemistry, 270, 7013(1995)

Non-patent Document 3: Science, 286, 735(1999)

Non-patent Document 4: Molecular and Cellular Neuroscience, 16,609(2000)

Non-patent Document 5: Journal of Medicinal Chemistry, 44, 2039(2001)

Patent Document 1: WO00/50391

Patent Document 2: WO01/70677

Patent Document 3: WO02/081433

Patent Document 4: WO02/081435

Patent Document 5: WO03/18543

Patent Document 6: JP-A-1997-95444

DISCLOSURE OF THE INVENTION Problems that the Invention is to Solve

An object of the present invention is to provide compounds having astructure different from that of the above-described known compounds,having an excellent inhibitory activity against production or secretionof β-amyloid protein and having desirable properties as pharmaceuticals.

Means for Solving the Problems

The present inventors have carried out various investigations. As aresult, it has been found that heterocyclic methylthio compounds,heterocyclic methyl sulfine compounds and heterocyclic methyl sulfonecompounds represented by the below-described formula (1) have anexcellent inhibitory activity against production or secretion ofβ-amyloid protein and are therefore useful as a medicament for treatingvarious diseases resulting from the abnormal production or secretion ofβ-amyloid protein, leading to the completion of the present invention.

In the present invention, there is thus provided a compound representedby the following formula (1):

(wherein, R¹ and R³ each independently represents an aromatichydrocarbon group which may have a substituent or an aromaticheterocyclic group which may have a substituent, R² represents asaturated or unsaturated monocyclic heterocyclic group or unsaturatedpolycyclic heterocyclic group which may have a substituent, R⁴represents a hydrogen atom or a C₁₋₆ alkyl group, and X represents —S—,—SO— or —SO₂—); an N-oxide or S-oxide thereof; a salt thereof; or asolvate thereof.

In the present invention, there is also provided a medicamentcontaining, as an effective ingredient, the compound represented by theformula (1); an N-oxide or S-oxide thereof; a salt thereof; or a solvatethereof.

In the present invention, there is also provided a pharmaceuticalcomposition containing the compound represented by the formula (1), anN-oxide or S-oxide thereof, a salt thereof, or a solvate thereof; and apharmaceutically acceptable carrier.

In the present invention, there is also provided use of the compoundrepresented by the formula (1), an N-oxide or S-oxide thereof, a saltthereof, or a solvate thereof for the preparation of a medicament.

In the present invention, there is also provided a method of treating adisease resulting from abnormal production or secretion of β-amyloidprotein, which comprises administering an effective amount of thecompound represented by the formula (1), an N-oxide or S-oxide thereof,a salt thereof, or a solvate thereof.

Advantageous Effect of the Invention

The present invention makes it possible to provide compounds having anexcellent inhibitory activity against production or section of β-amyloidprotein and having desirable properties as a medicament.

BEST MODE FOR CARRYING OUT THE INVENTION

The compound represented by the formula (1) is described bellow.

Examples of the aromatic hydrocarbon group represented by R¹ or R³include phenyl and naphthyl groups, of which phenyl group is preferred.

Examples of the aromatic heterocyclic group represented by R¹ or R³include 5- or 6-membered aromatic heterocyclic groups having 1 to 4atoms selected from nitrogen, oxygen and sulfur atoms. Specific examplesinclude pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, triazolyl,oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl,tetrazolyl, thiadiazolyl, pyrazinyl, and pyridazinyl groups.

Of these groups, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl,thiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, and pyridazinyl groupsare preferred; thienyl, pyridyl, pyrimidinyl and pyridazinyl groups aremore preferred; and thienyl, pyridyl and pyrimidinyl groups areespecially preferred.

Examples of the saturated monocyclic heterocyclic group represented byR² include 3- to 7-membered heterocyclic groups having 1 to 4 atomsselected from nitrogen, oxygen and sulfur atoms. Specific examplesinclude pyrrolidinyl, tetrahydrofuranyl, oxetanyl, tetrahydrothienyl,piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, thiomorpholinyl,aziridinyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl,tetrahydrothiopyranyl, dioxolanyl, oxathiolanyl and hexahydropyrimidinylgroups.

Of these, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, thiomorpholinyl,imidazolidinyl, pyrazolidinyl, tetrahydropyranyl andtetrahydrothiopyranyl groups are preferred; and piperidinyl,tetrahydropyranyl, tetrahydrothiopyranyl and hexahydropyrimidinyl groupsare more preferred.

Examples of the unsaturated monocyclic heterocyclic group represented byR² include 4- to 7-membered groups having 1 to 4 atoms selected fromnitrogen, oxygen and sulfur atoms. Specific examples include pyrrolyl,furyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl,isoxazolyl, isothiazolyl, triazinyl, tetrazolyl, thiadiazolyl,oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolinyl, pyrazolinyl, oxazolinyl, thiazolinyl, isoxazolinyl,isothiazolinyl, pyranyl, dihydropyridyl, tetrahydropyridyl,dihydropyrimidinyl, tetrahydropyridazinyl and tetrahydropyrimidinylgroups.

Of these, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, triazolyl,oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl,pyrazinyl, triazinyl, tetrazolyl, pyrrolinyl, imidazolinyl, pyrazolinyl,thiadiazolyl, pyrazinyl, pyridazinyl, tetrahydropyridyl,dihydropyrimidinyl and tetrahydropyridazinyl groups are preferred; andimidazolyl, pyridyl, pyrimidinyl and thiazolyl groups are morepreferred.

Examples of the unsaturated polycyclic heterocyclic group represented byR² include 8- to 10-membered groups having 1 to 4 atoms selected fromnitrogen, oxygen and sulfur atoms. Specific examples includebenzofuranyl, benzothiazolyl, indolyl, quinolyl, isoquinolyl,benzopyranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl,benzodioxanyl, benzothiophenyl, benzisothiazolyl, benzisoxazolyl,chromenyl, chromanyl, isochromenyl, isochromanyl, indolinyl, indazolyl,indolizinyl, isoindolyl, isoindolinyl, quinolizinyl, quinoxalinyl,quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, purinyl,tetrahydrothiazolopyridyl, imidazopyridyl, triazolopyridyl,pyrrolopyridyl, carbazolyl, xanthenyl, acridinyl, phenazinyl,phenoxazinyl, phenothiazinyl and quinuclidinyl groups.

Of these group, benzofuranyl, benzothiazolyl, indolyl, quinolyl,isoquinolyl, benzopyranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl,benzodioxanyl, benzothiophenyl, benzisothiazolyl, benzisoxazolyl,chromenyl, chromanyl, isochromenyl, isochromanyl, indolinyl, indazolyl,indolizinyl, quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl,phthalazinyl, naphthyridinyl, imidazopyridyl and triazolopyridyl groupsare preferred; and benzimidazolyl, chromenyl, imidazopyridyl andtriazolopyridyl groups are more preferred.

The aromatic hydrocarbon group or aromatic heterocyclic grouprepresented by R¹ or R³ may be substituted by 1 to 3 substituents, whichare the same or different, selected from halogen atoms, C₁₋₆ alkylgroups, trihalogenomethyl groups, C₁₋₆ alkoxy groups, C₂₋₆ alkenylgroups, formyl group, C₂₋₆ alkanoyl groups, carboxyl group, carboxyaminoC₁₋₆ alkyl groups, C₁₋₆ alkoxycarbonylamino C₁₋₆ alkyl groups, oxogroup, nitro group, cyano group, amidino group, C₂₋₆ alkenyloxy groups,hydroxy group, thioxo group, amino group, C₁₋₆ alkylamino groups,di(C₁₋₆ alkyl)amino groups, C₁₋₆ alkoxycarbonyl groups, carbamoyl group,C₁₋₆ alkylcarbamoyl groups, di(C₁₋₆ alkyl)carbamoyl groups,thiocarbamoyl group, C₁₋₆ alkylthiocarbamoyl groups, di(C₁₋₆alkyl)thiocarbamoyl groups, mercapto group, C₁₋₆ alkylthio groups, C₁₋₆alkylsulfinyl groups, C₁₋₆ alkylsulfonyl groups, and C₆₋₁₀ aromatichydrocarbon-C₁₋₆ alkyl groups.

As the substituent for the aromatic hydrocarbon group or aromaticheterocyclic group represented by R¹ or R³, halogen atoms, C₁₋₆ alkylgroups, trihalogenomethyl groups, C₁₋₆ alkoxy groups, cyano group,amidino group, hydroxy group, C₁₋₆ alkylamino groups, di(C₁₋₆alkyl)amino groups, carbamoyl group, C₁₋₆ alkylcarbamoyl groups anddi(C₁₋₆ alkyl)carbamoyl groups are preferred; halogen atoms, C₁₋₆ alkylgroups, trihalogenomethyl groups, C₁₋₆ alkoxy groups and cyano group aremore preferred; and halogen atoms and cyano group are especiallypreferred. Among the halogen atoms, chlorine and fluorine atoms arestill more preferred.

Examples of the substituent for the saturated or unsaturated monocyclicheterocyclic group or unsaturated polycyclic heterocyclic grouprepresented by R² include a group -Q¹⁰¹-Q¹⁰²-Q¹⁰³-Q¹⁰⁴-Q¹⁰⁵-Q¹⁰⁶-Q¹⁰⁷(wherein, Q¹⁰¹ represents a single bond, a C₁₋₆ alkylene group, a C₂₋₆alkenylene group or a heterocyclic group; Q¹⁰² represents a single bond,—O—, —NH—, —CH═—N—, —C(alkyl)═N—, —N(alkyl)- or —S—; Q¹⁰³ represents asingle bond, —CO—, —CS—, —SO—, —SO₂— or —CONH—; Q¹⁰⁴ represents a singlebond, a C₁₋₆ alkylene group, a C₂₋₆ alkenylene group, a C₃₋₈cyclolakylene group, a C₄₋₇ cycloalkenylene group, an aromatichydrocarbon group or a heterocyclic group; Q¹⁰⁵ represents a singlebond, —NH— or —N(alkyl)-; Q¹⁰⁶ represents a single bond, —O—, —CO—,—CS—, —SO₂—, —SO— or —S—; and Q¹⁰⁷ represents a hydrogen atom, a halogenatom, a hydroxy group, an oxo group, a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₃₋₇ cycloalkyl group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxygroup, an azide group, a cyano group, an amino group, a C₁₋₆ alkylaminogroup, a di(C₁₋₆ alkyl)amino group, a C₂₋₆ alkanoylamino group, adi(C₂₋₆ alkanoyl)amino group, a carboxyamino group, a C₁₋₆alkoxycarbonylamino group, a di(C₁₋₆ alkoxycarbonyl)amino group, aheterocyclic group, an aromatic hydrocarbon group, a C₄₋₇ cycloyalkenylgroup, a heterocycle-oxy group or an aromatic hydrocarbon-oxy group, inwhich the C₁₋₆ alkylene or alkyl group, C₂₋₆ alkenylene or alkenylgroup, C₃₋₇ cycloalkylene or C₃₋₇ cycloalkyl group, C₄₋₇ cycloalkenyleneor C₄₋₇ cycloalkenyl group, heterocyclic group, heterocycle-oxy group,aromatic hydrocarbon group or aromatic hydrocarbon-oxy group may besubstituted with 1 to 3 substituents selected from halogen atoms, C₁₋₆alkyl groups, C₁₋₆ alkoxy groups, C₂₋₆ alkenyl groups, carboxyamino C₁₋₆alkyl groups, C₁₋₆ alkoxycarbonylamino C₁₋₆ alkyl groups, formyl group,C₂₋₆ alkanoyl groups, oxo group, nitro group, cyano group, azide group,amidino group, C₂₋₆ alkenyloxy groups, hydroxy group, carboxyl group,C₇₋₁₆ aralkyl groups, thioxo group, C₂₋₆ alkanoyl groups, C₂₋₆thioalkanoyl groups, thioformyl group, amino group, C₁₋₆ alkylaminogroups, di(C₁₋₆ alkyl)amino groups, C₁₋₆ alkoxycarbonyl groups,carbamoyl group, C₁₋₆ alkylcarbamoyl groups, di(C₁₋₆ alkyl)carbamoylgroups, thiocarbamoyl group, C₁₋₆ alkylthiocarbamoyl groups, di(C₁₋₆alkyl)thiocarbamoyl groups, C₁₋₆ alkoxycarbamoylamino groups, C₁₋₆alkoxycarbamoyl(C₁₋₆ alkyl)amino groups, C₂₋₆ alkanoylamino groups, C₂₋₆alkanoyl(C₁₋₆ alkyl)amino groups, thio C₂₋₆ alkanoylamino groups, thioC₂₋₆ alkanoyl(C₁₋₆ alkyl)amino groups, formylamino group, formyl(C₁₋₆alkyl)amino groups, thioformylamino group, thioformyl(C₁₋₆ alkyl)aminogroups, C₂₋₆ alkanoyloxy groups, formyloxy group, C₁₋₆ alkoxycarbonyloxygroups, carbamoyloxy group, C₁₋₆ alkylcarbamoyloxy groups, di(C₁₋₆alkyl)carbamoyloxy groups, aminocarbonylamino group, C₁₋₆alkylaminocarbonylamino groups, di(C₁₋₆ alkyl)aminocarbonylamino groups,aminocarbonyl(C₁₋₆ alkyl)amino groups, C₁₋₆ alkylaminocarbonyl(C₁₋₆alkyl)amino groups, di(C₁₋₆ alkyl)aminocarbonyl(C₁₋₆ alkyl)amino groups,mercapto group, C₁₋₆ alkylthio groups, C₁₋₆ alkylsulfinyl groups, C₁₋₆alkylsulfonyl groups, aminosulfonyl group, C₁₋₆ alkylaminosulfonylgroups, di(C₁₋₆ alkyl)aminosulfonyl groups, aminosulfonylamino group,C₁₋₆ alkylaminosulfonylamino groups, di(C₁₋₆ alkyl)aminosulfonylaminogroups, aminosulfonyl(C₁₋₆ alkyl)amino groups, C₁₋₆alkylaminosulfonyl(C₁₋₆ alkyl)amino groups and di(C₁₋₆alkyl)aminosulfonyl(C₁₋₆ alkyl)amino groups.

The substituents for the heterocyclic group represented by R² aredescribed more specifically as follows.

The heterocyclic group represented by R² may be substituted with 1 to 3substituents selected from halogen atoms, cyano group, C₁₋₆ alkylgroups, hydroxy group, C₁₋₆ alkoxy groups, C₂₋₆ alkenyloxy groups,carboxy C₁₋₆ alkyl groups, C₁₋₆ alkoxycarbonyl C₁₋₆ alkyl groups,heterocyclecarbonyl C₁₋₆ alkyl groups, hydroxy C₁₋₆ alkyl groups, C₆₋₁₀aromatic hydrocarbon-sulfonyl C₁₋₆ alkyl groups,N,N-dialkylaminosulfonyl C₁₋₆ alkyl groups, heterocycle-C₁₋₆ alkylgroups, C₆₋₁₀ aromatic hydrocarbon-C₁₋₆ alkyl groups, C₆₋₁₀ aromatichydrocarbon-thio C₁₋₆ alkyl groups, azido-C₁₋₆ alkyl groups, amino C₁₋₆alkyl groups, C₁₋₆ alkylamino C₁₋₆ alkyl groups, di(C₁₋₆ alkyl)aminoC₁₋₆ alkyl groups, hydroxy C₁₋₆ alkylamino C₁₋₆ alkyl groups, C₁₋₆alkoxy C₁₋₆ alkylaminoC₁₋₆ alkyl groups, di(C₁₋₁₆ alkoxyC₁₋₆ alkyl)aminoC₁₋₆ alkyl groups, N-hydroxy C₁₋₆ alkyl-N—C₁₋₆ alkoxy C₁₋₆ alkylaminoC₁₋₆ alkyl groups, C₂₋₆ alkanoylamino C₁₋₆ alkyl groups, di(C₂₋₆alkanoyl)amino C₁₋₆ alkyl groups, carboxyamino C₁₋₆ alkyl groups,di(C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl)amino C₁₋₆ alkyl groups, C₁₋₆alkoxycarbonylamino C₁₋₆ alkyl groups, di(C₁₋₆ alkoxycarbonyl)amino C₁₋₆alkyl groups, carbamoylamino C₁₋₆ alkyl groups, N—C₁₋₆alkylcarbamoylamino C₁₋₆ alkyl groups, (N,N-di(C₁₋₆alkyl)carbamoyl)amino C₁₋₆ alkyl groups, aminosulfonylamino C₁₋₆ alkylgroups, N—C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl groups, (di(C₁₋₆alkyl)aminosulfonyl)amino C₁₋₆ alkyl groups, C₆₋₁₀ aromatichydrocarbon-sulfonylamino-C₂₋₆ alkanoylamino C₁₋₆ alkyl groups, aminoC₁₋₆ alkylcarbonylamino C₁₋₆ alkyl groups, N—C₁₋₆ alkylamino C₁₋₆alkylcarbonylamino C₁₋₆ alkyl groups, N,N-di(C₁₋₆ alkyl)amino C₁₋₆alkylcarbonylamino C₁₋₆ alkyl groups, heterocycle-C₁₋₆alkylcarbonylamino C₁₋₆ alkyl groups, heterocycle-C₂₋₆alkenylcarbonylamino C₁₋₆ alkyl groups, C₆₋₁₀ aromatic hydrocarbon-C₂₋₆alkenylcarbonylamino C₁₋₆ alkyl groups, C₆₋₁₀ aromatichydrocarboncarbonylamino C₁₋₆ alkyl groups, C₆₋₁₀ aromatichydrocarbonthiocarbonylamino C₁₋₆ alkyl groups, heterocyclecarbonylaminoC₁₋₆ alkyl groups, C₁₋₆ alkoxyoxalylamino C₁₋₆ alkyl groups, N—(C₆₋₁₀aromatic hydrocarbon-sulfonyl)-N-C₁₋₆ alkylamino C₁₋₆ alkyl groups, C₁₋₆alkylsulfonylamino C₁₋₆ alkylamino groups, carbamoyloxy C₁₋₆ alkylgroups, N—C₁₋₆ alkylcarbamoyloxy C₁₋₆ alkyl groups, N,N-di(C₁₋₆alkyl)carbamoyloxy C₁₋₆ alkyl groups, C₆₋₁₀ aromatic hydrocarbon-C₁₋₆alkylcarbamoyloxy C₁₋₆ alkyl groups, C₁₋₆ alkoxycarbonyloxy-C₁₋₆ alkylgroups, C₆₋₁₀ aromatic hydrocarbon oxycarbonyloxy C₁₋₆ alkyl groups,heterocyclic carbonylhydrazonomethyl groups, C₆₋₁₀ aromatic hydrocarboncarbonylhydrazonomethyl groups, C₂₋₆ alkenyl groups, carboxy-C₂₋₆alkenyl groups, C₁₋₆ alkoxycarbonyl-C₂₋₆ alkenyl groups, carbamoyl C₂₋₆alkenyl groups, heterocycle-C₂₋₆ alkenyl groups, formyl group, carboxylgroup, heterocycle-carbonyl groups, C₆₋₁₀ aromatic hydrocarbon-carbonylgroups, C₁₋₆ alkoxycarbonyl groups, carbamoyl group, N—C₁₋₆alkylcarbamoyl groups, N,N-di(C₁₋₆ alkyl) carbamoyl groups, (C₃₋₇cycloalkyl-C₁₋₆ alkyl)carbamoyl groups, C₁₋₆ alkylthio C₁₋₆alkylcarbamoyl groups, C₁₋₆ alkylsulfinyl C₁₋₆ alkylcarbamoyl groups,C₁₋₆ alkylsulfonyl C₁₋₆ alkylcarbamoyl groups, hydroxyaminocarbonylgroup, C₁₋₆ alkoxycarbamoyl groups, hydroxy C₁₋₆ alkylcarbamoyl groups,C₁₋₆ alkoxy C₁₋₆ alkylcarbamoyl groups, amino C₁₋₆ alkylcarbamoylgroups, amino C₁₋₆ alkylthiocarbamoyl groups, hydroxy C₁₋₆alkylcarbamoyl groups, C₁₋₆ alkoxycarbonyl C₁₋₆ alkylcarbamoyl groups,(C₁₋₆ alkoxycarbonylamino)C₁₋₆ alkylcarbamoyl groups, (C₁₋₆alkoxycarbonylamino)C₁₋₆ alkylthiocarbamoyl groups,heterocycle-carbamoyl groups, heterocycle-C₁₋₆ alkylcarbamoyl groups,C₆₋₁₀ aromatic hydrocarbon-carbamoyl groups, hydrazinocarbonyl groups,N—C₁₋₆ alkylhydrazinocarbonyl groups, N′—C₁₋₆ alkylhydrazinocarbonylgroups, N′,N′-di(C₁₋₆ alkyl)hydrazinocarbonyl groups, N,N′-di(C₁₋₆alkyl)hydrazinocarbonyl groups, N,N′,N′-tri(C₁₋₆ alkyl)hydrazinocarbonylgroups, N′-(heterocycle-carbonyl)-hydrazinocarbonyl groups, amino group,C₁₋₆ alkoxy C₁₋₆ alkylamino groups, amino C₁₋₆ alkylamino groups, (C₁₋₆alkylamino C₁₋₆ alkyl)amino groups, N—C₁₋₆ alkylamino C₁₋₆ alkyl-N—C₁₋₆alkylamino groups, (C₁₋₆ alkoxycarbonylamino C₁₋₆ alkyl)amino groups,(di(C₁₋₆ alkyl)amino C₁₋₆ alkyl)amino groups, heterocycle-amino C₁₋₆alkylamino groups, carboxyl C₁₋₆ alkylamino groups, N-carboxyl C₁₋₆alkyl-N—C₁₋₆ alkylamino groups, heterocycle-C₁₋₆ alkylamino groups,N-(heterocycle-C₁₋₆ alkyl)-N—C₁₋₆ alkylamino groups, hydroxyC₁₋₆alkylamino groups, N-hydroxy C₁₋₆ alkyl-N—C₁₋₆ alkylamino groups, (C₁₋₆alkylthio C₁₋₆ alkyl)amino groups, (C₁₋₆ alkylcarbamoyloxy C₁₋₆alkyl)amino groups, N—C₁₋₆ alkylaminocarbonyloxy C₁₋₆ alkyl-N—C₁₋₆alkylamino groups, C₁₋₆ alkylsulfinyl C₁₋₆ alkylamino groups, C₁₋₆alkylsulfonyl C₁₋₆ alkylamino groups, groups represented by the formula:—N(R¹²)SO₂R¹¹ (wherein, R¹¹ represents a C₁₋₆ alkyl group, heterocyclicgroup, C₁₋₆ alkyl-heterocyclic group, heterocycleC₁₋₆ alkyl group,hydroxy C₁₋₆ alkyl group, amino C₁₋₆ alkyl group, C₁₋₆ alkylamino C₁₋₆alkyl group, di(C₁₋₆ alkyl)amino C₁₋₆ alkyl group, carboxy C₁₋₆ alkylgroup, carbamoyl C₁₋₆ alkyl group, trifluoromethyl group, difluoromethylgroup, fluoromethyl group, amino group, C₁₋₆ alkylamino group or di(C₁₋₆alkyl)amino group, and R¹² represents a hydrogen atom, C₁₋₆ alkyl group,hydroxy group or amino group), hydroxy C₁₋₆ alkoxy C₁₋₆ alkylaminogroups, C₆₋₁₀ aromatic hydrocarbon-C₁₋₆ alkylamino groups,heterocycle-carbonylamino groups, C₁₋₆ alkoxycarbonylamino groups,heterocycle-C₁₋₆ alkylcarbonylamino groups, C₆₋₁₀ aromatichydrocarboncarbonylamino groups, heterocycle-amino groups, hydroxyiminogroup, C₁₋₆ alkoxyimino groups, oxo group, hydroxyimino C₁₋₆ alkylgroups, C₁₋₆ alkoxycarbonyl C₁₋₆ alkylamino groups, (C₂₋₆ alkanoylaminoC₁₋₆ alkyl)amino groups, C₆₋₁₀ aromatic hydrocarbon groups, andheterocyclic groups (in which, the C₆₋₁₀ aromatic hydrocarbon group orheterocycle or heterocyclic group may be substituted with 1 to 3substituents selected from halogen atoms, C₁₋₆ alkyl groups, C₁₋₆ alkoxygroups, C₂₋₆ alkenyl groups, formyl group, C₂₋₆ alkanoyl groups,carboxyl group, carboxyamino C₁₋₆ alkyl groups, C₁₋₆ alkoxycarbonylaminoC₁₋₆ alkyl groups, oxo group, nitro group, cyano group, amidino group,C₂₋₆ alkenyloxy groups, hydroxy group, thioxo group, amino group, C₁₋₆alkylamino groups, di(C₁₋₆ alkyl)amino groups, amino C₁₋₆ alkyl groups,C₁₋₆ alkoxycarbonyl groups, carbamoyl group, C₁₋₆ alkylcarbamoyl groups,di(C₁₋₆ alkyl)carbamoyl groups, thiocarbamoyl group, C₁₋₆alkylthiocarbamoyl groups, di(C₁₋₆ alkyl)thiocarbamoyl groups, C₂₋₆alkanoylamino groups, C₂₋₆ alkanoyl(C₁₋₆ alkyl)amino groups, thio C₂₋₆alkanoylamino groups, thio C₂₋₆ alkanoyl(C₁₋₆ alkyl)amino groups,formylamino group, formyl(C₁₋₆ alkyl)amino groups, thioformylaminogroup, thioformyl(C₁₋₆ alkyl)amino groups, C₂₋₆ alkanoyloxy groups,formyloxy group, mercapto group, C₁₋₆ alkylthio groups, C₁₋₆alkylsulfinyl groups, C₁₋₆ alkylsulfonyl groups, aminosulfonyl groups,C₁₋₆ alkylaminosulfonyl groups, di(C₁₋₆ alkyl)aminosulfonyl groups, C₁₋₆alkylsulfonylamino groups, C₁₋₆ alkylsulfonyl(C₁₋₆ alkyl)amino groups,and hydroxy C₁₋₆ alkyl groups).

The heterocyclic group represented by R² is preferably substituted with1 to 3, more preferably 2 substituents selected from halogen atoms,cyano group, C₁₋₆ alkyl groups, hydroxy group, C₁₋₆ alkoxy groups, C₂₋₆alkenyloxy groups, carboxy C₁₋₆ alkyl groups, C₁₋₆ alkoxycarbonyl C₁₋₆alkyl groups, hydroxy C₁₋₆ alkyl groups, C₆₋₁₀ aromatichydrocarbon-sulfonyl C₁₋₆ alkyl groups, heterocycle-C₁₋₆ alkyl groups,C₆₋₁₀ aromatic hydrocarbon-C₁₋₆ alkyl groups, C₆₋₁₀ aromatichydrocarbon-thio C₁₋₆ alkyl groups, azido-C₁₋₆ alkyl groups, amino C₁₋₆alkyl groups, di(C₁₋₆ alkyl)amino C₁₋₆ alkyl groups, di(C₁₋₆ alkoxy C₁₋₆alkyl)amino C₁₋₆ alkyl groups, C₂₋₆ alkanoylamino C₁₋₆ alkyl groups,di(C₂₋₆ alkanoyl)amino C₁₋₆ alkyl groups, C₁₋₆ alkoxycarbonylamino C₁₋₆alkyl groups, di(C₁₋₆ alkoxycarbonyl)amino C₁₋₆ alkyl groups,(N,N-di(C₁₋₆ alkyl)carbamoyl)amino C₁₋₆ alkyl groups, N—C₁₋₆alkylsulfonylamino C₁₋₆ alkyl groups, (di(C₁₋₆ alkyl)aminosulfonyl)aminoC₁₋₆ alkyl groups, C₆₋₁₀ aromatic hydrocarbon-sulfonylaminoC₂₋₆alkanoylamino C₁₋₆ alkyl groups, N,N-di(C₁₋₆ alkyl)aminoC₁₋₆alkylcarbonylamino C₁₋₆ alkyl groups, heterocycle-C₁₋₆alkylcarbonylamino C₁₋₆ alkyl groups, heterocycleC₂₋₆alkenylcarbonylamino C₁₋₆ alkyl groups, C₆₋₁₀ aromatichydrocarbon-carbonylamino C₁₋₆ alkyl groups, C₆₋₁₀ aromatichydrocarbon-thiocarbonylamino C₁₋₆ alkyl groups,heterocycle-carbonylamino C₁₋₆ alkyl groups, C₁₋₆ alkoxyoxalylamino C₁₋₆alkyl groups, N—(C₆₋₁₀ aromatic hydrocarbon-sulfonyl)-N—C₁₋₆ alkylaminoC₁₋₆ alkyl groups, C₁₋₆ alkylsulfonylamino C₁₋₆ alkylamino groups,N,N-di(C₁₋₆ alkyl)carbamoyloxy C₁₋₆ alkyl groups, C₆₋₁₀ aromatichydrocarbon-C₁₋₆ alkylcarbamoyloxy C₁₋₆ alkyl groups, C₁₋₆alkoxycarbonyloxy-C₁₋₆ alkyl groups, C₆₋₁₀ aromatichydrocarbon-oxycarbonyloxy C₁₋₆ alkyl groups, carboxy-C₂₋₆ alkenylgroups, C₁₋₆ alkoxycarbonyl-C₂₋₆ alkenyl groups, carbamoyl C₂₋₆ alkenylgroups, heterocycle-C₂₋₆ alkenyl groups, formyl group, carboxyl group,heterocyclecarbonyl groups, C₁₋₆ alkoxycarbonyl groups, carbamoyl group,N,N-di(C₁₋₆ alkyl)carbamoyl groups, (C₃₋₇ cycloalkylC₁₋₆ alkyl)carbamoylgroups, C₁₋₆ alkylthio C₁₋₆ alkylcarbamoyl groups, C₁₋₆ alkylsulfinylC₁₋₆ alkylcarbamoyl groups, C₁₋₆ alkylsulfonyl C₁₋₆ alkylcarbamoylgroups, C₁₋₆ alkoxycarbamoyl groups, amino C₁₋₆ alkylcarbamoyl groups,amino C₁₋₆ alkylthiocarbamoyl groups, hydroxy C₁₋₆ alkylcarbamoylgroups, C₁₋₆ alkoxycarbonyl C₁₋₆ alkylcarbamoyl groups, (C₁₋₆alkoxycarbonylamino)C₁₋₆ alkylcarbamoyl groups, (C₁₋₆alkoxycarbonylamino)C₁₋₆ alkylthiocarbamoyl groups, heterocyclecarbamoylgroups, heterocycle-C₁₋₆ alkylcarbamoyl groups, N′,N′-di(C₁₋₆alkyl)hydrazinocarbonyl groups,N′-(heterocycle-carbonyl)-hydrazinocarbonyl groups, amino group, C₁₋₆alkoxy C₁₋₆ alkylamino groups, amino C₁₋₆ alkylamino groups, C₁₋₆alkylamino C₁₋₆ alkylamino groups, (C₁₋₆ alkylamino C₁₋₆ alkyl)(C₁₋₆alkyl)amino groups, C₁₋₆ alkoxycarbonylamino C₁₋₆ alkylamino groups,di(C₁₋₆ alkyl)amino C₁₋₆ alkylamino groups, heterocycle-amino C₁₋₆alkylamino groups, carboxyl C₁₋₆ alkylamino groups, (carboxyl C₁₋₆alkyl)(C₁₋₆ alkyl)amino groups, heterocycle-C₁₋₆ alkylamino groups(heterocycle-C₁₋₆ alkyl)(C₁₋₆ alkyl)amino groups, hydroxy C₁₋₆alkylamino groups, (hydroxy C₁₋₆ alkyl)(C₁₋₆ alkyl)amino groups, C₁₋₆alkylthio C₁₋₆ alkylamino groups, C₁₋₆ alkylaminocarbonyloxy C₁₋₆alkylamino groups, (C₁₋₆ alkylaminocarbonyloxy C₁₋₆ alkyl)(C₁₋₆alkyl)amino groups, C₁₋₆ alkylsulfinyl C₁₋₆ alkylamino groups, C₁₋₆alkylsulfonyl C₁₋₆ alkylamino groups, groups represented by the formula:—N(R¹²)SO₂R¹¹ (wherein, R¹¹ represents a C₁₋₆ alkyl group, heterocyclicgroup, C₁₋₆ alkyl-heterocyclic group, heterocycle-C₁₋₆ alkyl group,hydroxy C₁₋₆ alkyl group, amino C₁₋₆ alkyl group, C₁₋₆ alkylamino C₁₋₆alkyl group, di(C₁₋₆ alkyl)amino C₁₋₆ alkyl group, carboxy C₁₋₆ alkylgroup, carbamoyl C₁₋₆ alkyl group, trifluoromethyl group, difluoromethylgroup, fluoromethyl group, amino group, C₁₋₆ alkylamino group or di(C₁₋₆alkyl)amino group, and R¹² represents a hydrogen atom, C₁₋₆ alkyl group,hydroxy group or amino group), hydroxy C₁₋₆ alkoxy C₁₋₆ alkylaminogroups, C₆₋₁₀ aromatic hydrocarbon-C₁₋₆ alkylamino groups,heterocycle-carbonylamino groups, C₁₋₆ alkoxycarbonylamino groups,heterocycle-alkylcarbonylamino groups, C₆₋₁₀ aromatichydrocarbon-carbonylamino groups, oxo group, hydroxyimino C₁₋₆ alkylgroups, C₁₋₆ alkoxycarbonyl C₁₋₆ alkylamino groups, (C₂₋₆ alkanoylaminoC₁₋₆ alkyl)amino groups, C₆₋₁₀ aromatic hydrocarbon groups, andheterocyclic groups (in which, the C₆₋₁₀ aromatic hydrocarbon group orheterocyclic group may be substituted with 1 to 3 substituents selectedfrom halogen atoms, C₁₋₆ alkyl groups, C₁₋₆ alkoxy groups, C₂₋₆ alkanoylgroups, oxo group, nitro group, cyano group, hydroxy group, amino C₁₋₆alkyl groups, C₁₋₆ alkoxycarbonyl groups, formylamino group, and hydroxyC₁₋₆ alkyl groups).

As R², more preferred is a group represented by the following formula:

(wherein, R¹⁰ represents a hydrogen atom, C₁₋₆ alkyl group, hydroxy C₁₋₆alkyl group, C₁₋₆ alkylsulfinyl C₁₋₆ alkyl group, C₁₋₆ alkylsulfonylC₁₋₆ alkyl group, carboxy C₁₋₆ alkyl group, heterocycle-C₁₋₆ alkylgroup, or a group represented by the formula: —SO₂—R¹¹ (in which, R¹¹represents a C₁₋₆ alkyl, heterocyclic, C₁₋₆ alkyl-heterocyclic,heterocycle-C₁₋₆ alkyl, hydroxy C₁₋₆ alkyl, amino C₁₋₆ alkyl, C₁₋₆alkylamino C₁₋₆ alkyl, di(C₁₋₆ alkyl)amino C₁₋₆ alkyl, carboxy C₁₋₆alkyl, carbamoyl C₁₋₆ alkyl, trifluoromethyl, difluoromethyl,fluoromethyl, amino, C₁₋₆ alkylamino, or di(C₁₋₆ alkyl)amino group), R¹²represents a hydrogen atom, C₁₋₆ alkyl group, hydroxy group, or aminogroup, or R¹¹ and R¹² may, taken together with a sulfur atom to whichR¹¹ is attached and a nitrogen atom to which R¹² is attached, form a 5-or 6-membered aliphatic heterocycle, and R¹³ represents a C₁₋₆ alkylgroup, halogen atom or cyano group).

As R², a group represented by the following formula:

(wherein, R¹³ represents a C₁₋₆ alkyl group, halogen atom or cyano groupand n stands for an integer of from 0 to 6) is also preferred.

As R⁴, a hydrogen atom is especially preferred. As X, —SO₂— and —SO— arepreferred from the standpoint of its pharmacological effect, of which—SO₂— is especially preferred from the standpoint of its pharmacologicaleffect.

Substituents for the aromatic hydrocarbon group or aromatic heterocyclicgroup represented by R¹ or R³, and substituents for the saturated orunsaturated monocyclic heterocyclic group or unsaturated polycyclicheterocyclic group represented by R² will next be describedspecifically.

The term “heterocycle” means a cycle having from 1 to 4 hetero atoms (N,O, S, etc.) as a component of its cyclic structure and it may be any oneof a saturated, unsaturated or aromatic cycle, or may be either one of amonocyle or polycycle. The polycyclic heterocycle embraces aheterocyclic spiro compound and a heterocyclic compound having acrosslinked cyclic structure. The term “heterocycle” in the descriptionof “heterocycle-C₁₋₆ alkyl group” and the like means a heterocyclicgroup introduced from the above-described heterocycle. The term“heterocyclic group” means a monovalent group introduced from“heterocycle”.

Examples of the saturated monocylic heterocyclic group include 3- to7-membered ones having 1 to 4 atoms selected from nitrogen, oxygen andsulfur atoms. Specific examples include pyrrolidinyl, tetrahydrofuranyl,oxetanyl, tetrahydrothienyl, piperidinyl, piperazinyl, homopiperazinyl,morpholinyl, thiomorpholinyl, oxiranyl, thiolanyl, dioxanyl, aziridinyl,imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl,oxazolidinyl, thiazolidinyl, isoxazolidinyl, isothiazolidinyl,dioxolanyl, oxathiolanyl, and hexahydropyrimidinyl groups.

Examples of the unsaturated or aromatic monocyclic heterocyclic groupinclude 4- to 7-membered ones having 1 to 4 atoms selected fromnitrogen, oxygen and sulfur atoms. Specific examples include pyrrolyl,furyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl,isoxazolyl, isothiazolyl, triazinyl, tetrazolyl, thiadiazolyl,oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl pyridazinyl, pyrrolidinyl,imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl,isoxazolidinyl, isothiazolidinyl, pyranyl, dihydropyridyl,tetrahydropyridyl, dihydropyridazinyl, dihydropyrimidinyl,tetrahydropyridazinyl and tetrahydropyrimidinyl.

Examples of the polycyclic heterocyclic group include 8- to 14-memberedones having 1 to 4 atoms selected from nitrogen, oxygen and sulfuratoms. Specific examples include benzofuranyl, benzothiazolyl, indolyl,quinolyl, isoquinolyl, benzopyranyl, benzoxazolyl, benzothiazolyl,benzimidazolyl, benzodioxanyl, benzothiophenyl, benzisothiazolyl,benzisoxazolyl, chromenyl, chromanyl, isochromenyl, isochromanyl,indolinyl, indazolyl, indolizinyl, isoindolyl, isoindolinyl,quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl,naphthyridinyl, purinyl, tetrahydrothiazolopyridyl, imidazopyridyl,pyrrolopyridyl, carbazolyl, xanthenyl, acridinyl, phenazinyl,phenoxazinyl, phenothiazinyl and quinuclidinyl groups.

The term “halogen atoms” means chlorine, fluorine, bromine and iodineatoms, of which chlorine and fluorine atoms are preferred.

The term “C₁₋₆ alkyl group” means a linear or branched C₁₋₆ alkyl group.Specific examples of the alkyl group include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, 2-methylpentyland n-hexyl.

The term “C₁₋₆ alkylene group” means a linear or branched C₁₋₆ alkylenegroup. Specific examples of the alkylene group include methylene,ethylene, propylene, trimethylene, tetramethylene, pentamethylene andhexamethylene.

The term “C₂₋₆ alkenyl group” means a linear or branched C₂₋₆ alkenylgroup. Specific examples of the alkenyl group include vinyl, allyl,propenyl, butenyl and pentenyl.

The term “C₂₋₆ alkenylene group” means a linear or branched C₂₋₆alkenylene group. Specific examples of the alkenylene group includevinylene, propenylene, butenine, and pentenylene.

Examples of the “C₃₋₇ cycloalkyl group” include C₃₋₇ cycloalkyl groupssuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl.

Examples of the C₄₋₇ cycloalkenyl group include C₄₋₇ cycloalkenyl groupssuch as cyclopentenyl and cyclohexenyl.

Examples of the combination of a cycloalkyl group and an alkyl groupinclude cycloalkyl-alkyl groups, of which C₃₋₇ cycloalkyl-C₁₋₆ alkylgroups are especially preferred.

The term “C₁₋₇ alkoxy group” means an alkoxy group having theabove-described alkyl or cycloalkyl group. Examples include methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, cyclopentyloxy,cyclohexyloxy, and cycloheptyloxy.

The term “C₂₋₆ alkanoyl group” means a linear or branched C₂₋₆ alkanoylgroup and examples include acetyl, propionyl, butyryl, valeryl, andhexanoyl.

As R¹, 2,5-difluorophenyl or 2-fluoro-5-cyanophenyl group is especiallypreferred. As R³, 4-chlorophenyl, 4-fluorophenyl, 2,4-difluorophenyl,3,4-difluorophenyl, 3-fluoro-4-chlorophenyl, 4-trifluoromethylphenyl,5-chloro-2-thienyl, 5-chloro-2-pyridyl, 6-chloro-3-pyridyl and6-trifluoromethyl-3-pyridyl groups are especially preferred.

The compounds of the present invention represented by the formula (1)may have a stereoisomer or an enantiomer derived from an asymmetrichydrocarbon. Any one of the stereoisomer and enantiomer, and mixturethereof are all embraced in the present invention. The S-oxide of thecompound of the invention exists when the heterocyclic group contains asulfur atom. Either one of a monoxide or dioxide is embraced in theS-oxide.

No particular limitation is imposed on the salt of the compound of thepresent invention represented by the formula (1) insofar as it is apharmaceutically acceptable salt. Specific examples of the salt includemineral acid salts such as hydrochloride, hydrobromide, hydroiodide,phosphate, nitrate and sulfate, organic sulfonates such asmethanesulfonate, 2-hydroxyethanesulfonate and p-toluenesulfonate, andorganic carboxylates such as benzoate, acetate, propanoate, oxalate,malonate, succinate, glutarate, adipate, tartrate, maleate, malate andmandelate.

When the compound represented by the formula (1) has an acid group, thecompound may be a salt of an alkali metal ion or alkaline earth metalion. No particular limitation is imposed on the solvate insofar as it ispharmaceutically acceptable. Specific examples of it include hydratesand ethanol solvates.

Preparation processes of the compounds of the present inventionrepresented by the formula (1) will next be described.

The compounds of the present invention represented by the formula (1) orsalts thereof, or solvates thereof can be prepared using generally knownchemical preparation processes in combination. Typical synthesisprocesses will next be described.

Typical preparation processes of a sulfide compound (1a), a sulfinylcompound (1b) and a sulfonyl compound (1c) according to the presentinvention represented by the formula (1) will hereinafter be described.

1) Preparation Process of Sulfide Compound (1a)

The sulfide compound (1a) in the present invention can be prepared bythe below-described process.

(wherein, Y represents an eliminating group and R¹ to R⁴ have the samemeanings as described above.)

The sulfide compound (1a) of the present invention can be prepared bytransferring an alcohol derivative (2) to a compound (3), and thenreacting the resulting compound (3) with a thiol compound (R³—SH) in thepresence of a base. In this case, the thiol compound may be used as analkali metal or alkaline earth metal salt (for example, lithium salt,sodium salt or potassium salt).

The reaction temperature of the compound (3) and thiol compound (R³—SH)is usually from −20 to 200° C., preferably from room temperature to 100°C. The reaction temperature higher than the above-described range issometimes preferred, depending on the compound (3) or thiol compound(R³—SH). The reaction in a sealed tube is sometimes preferred. Thereaction time usually ranges from 0.5 hour to a day.

Examples of the base include hydrides of an alkali metal or alkalineearth metal (such as lithium hydride, sodium hydride, potassium hydrideand calcium hydride); amides of an alkali metal or alkaline earth metal(such as lithium amide, sodium amide, lithium diisopropylamide, lithiumdicyclohexylamide, lithium hexamethyldisilazide, sodiumhexamethyldisilazide and potassium hexamethyldisilazide); loweralkoxides of an alkali metal or alkaline earth metal (such as sodiummethoxide, sodium ethoxide and potassium t-butoxide); hydroxides of analkali metal, alkaline earth metal or silver (such as silver hydroxide,sodium hydroxide, potassium hydroxide, lithium hydroxide and bariumhydroxide); carbonates of an alkali metal, alkaline earth metal orsilver (sodium carbonate, potassium carbonate, cesium carbonate andsilver carbonate); bicarbonates of an alkali metal (such as sodiumbicarbonate and potassium bicarbonate); alkyl lithiums (such as n-butyllithium) or alkyl Grignard reagents (such as methyl magnesium bromide);inorganic bases such as silver oxide, or amines (such as triethylamine,diisopropylethylamine and N-methylmorpholine); and organic bases, forexample, basic heterocyclic compounds (such as dimethylaminopyridine,pyridine, imidazole, 2,6-lutidine, collidine,1,8-diazabicyclo[5.4.0]undece-7-en, 1,5-diazabicyclo[4.3.0]non-5-en, and1,4-diazabicyclo[2.2.2]octane).

Examples of the solvent include alcohol solvents, ether solvents,halogen solvents, aromatic solvents, nitrile solvents, amide solvents,ketone solvents, sulfoxide solvents and water. Two of these solvents maybe used as a mixture. Of these, methylene chloride, tetrahydrofuran anddimethylformamide are preferred.

The alcohol derivative (2) used in the above-described preparation stepcan be prepared in a known manner. Various processes are known and oneexample will next be described. The alcohol derivative (2) is availableby adding an organometal reagent (typically, an organolithium reagentrepresented by R²—Li, or a Grignard reagent represented by R²—MgCl,R²—MgBr or the like) in an amount of from equivalent to excess to analdehyde or ketone represented by R¹(C═O)—R⁴ in a solvent such astetrahydrofuran or diethyl ether to react them. The above-describedorganometal reagent can be readily prepared, for example, when R²represents an aromatic hydrocarbon group or an aromatic heterocyclicgroup, by adding an alkyl lithium reagent or alkyl Grignard reagent toan aryl halide or a heteroaryl halide to cause metal exchange, asreported in the thesis of H. Gilman, et. al., J. Org. Chem., 16,1788-1791(1951), or in the thesis of F. Trecourt, et al., Tetrahedron,56, 1349-1460(2000).

The compound (3) having an eliminating group Y can be prepared byconverting the hydroxyl group of the alcohol derivative (2) to aneliminating group in a known manner. Examples of the eliminating grouprepresented by Y include halogen atoms (such as chlorine, bromine andiodine), C₁₋₆ alkylsulfonyloxy groups which may be halogenated (such asmethanesulfonyloxy, ethanesulfonyloxy and trifluoromethanesulfonyloxy),and C₆₋₁₀ aromatic hydrocarbon sulfonyloxy groups which may have asubstituent. Substituents for the aromatic hydrocarbon sulfonyloxy groupinclude 1 to 3 halogen atoms, C₁₋₆ alkyl groups which may be halogenatedand C₁₋₆ alkoxy groups. Preferred examples of the eliminating groupinclude benzenesulfonyloxy, p-toluenesulfonyloxy,1-naphthalenesulfonyloxy and 2-naphthalensulfonyloxy.

As an alternate synthesizing process of the sulfide compound (1a), theMitsunobu reaction between the alcohol derivative (2) and a thiolcompound (R³—H) can be mentioned. Described specifically, the compound(1a) can be prepared by reacting between the alcohol derivative (2) and1 to 3 equivalents of the thiol compound (R³—SH) in a solvent in thepresence of both 1 to 3 equivalents of a triarylphosphine (such astriphenylphosphine) or trialkylphosphine (such as tributylphosphine) and1 to 2 equivalents of an azodicarboxylic acid compound (such as diethylazodicarboxylate, diisopropyl azodicarboxylate, azodicarboxylic aciddipiperidineamide or azodicarboxylic acid bisdimethylamide).

The reaction temperature is usually from −20° C. to 150° C., preferablyfrom 0 to 80° C. The reaction time usually ranges from 0.5 hour to 5days. Examples of the solvent include ether solvents, halogen solventsand aromatic solvents. Two or more of these solvents may be used as amixture. Of these, tetrahydrofuran is preferred.

2) Preparation Process of Sulfinyl Compound (1b)

The sulfinyl compound (1b) in the present invention can be prepared, asdescribed below, by oxidizing the sulfide compound (1a) with anoxidizing agent in a solvent.

(wherein, R¹ to R⁴ each has the same meaning as described above).

The reaction temperature usually ranges from −20° C. to 200° C.,preferably from 0 to 100° C. The reaction time usually ranges from 0.1hour to 7 days, preferably from 0.5 hour to 2 days. Examples of thesolvent include alcohol solvents, ether solvents, halogen solvents,aromatic solvents, nitrile solvents, amide solvents, ketone solvents,sulfoxide solvents and water. Two or more of these solvents may be usedas a mixture. Of these, methylene chloride, chloroform, methanol andethanol are preferred.

Examples of the oxidizing agent include hydrogen peroxide, organicperacid compounds (such as peracetic acid and meta-chloroperbenzoicacid), metaperiodates (such as sodium metaperiodate), acyl nitrate,dinitrogen tetroxide, halogens, N-halogen compounds (such asN-chlorosuccinimide and N-bromosuccinimide), hydroperoxides (such ast-butylhydroperoxide), iodobenzene diacetate, iodobenzene dichloride,t-butyl hypochlorite, sulfuryl chloride, singlet oxygen, ozone, seleniumoxide, and seleninic acid.

Specific reaction conditions are as follows. The sulfinyl compound (1b)can be prepared by treating the sulfide compound (1a) with from 1 to 2equivalents of metachloroperbenzoic acid, sodium periodate or hydrogenperoxide in a solvent such as methylene chloride, tetrahydrofuran-water,methanol or the like at 0 to 100° C. for about 1 hour to 2 days.

An optically active sulfoxide (1b) can be prepared by using titaniumtetraisopropoxide/optically pure diethyl tartrate/t-butylhydroperoxide,titanium tetraisopropoxide/optically pure diethyl tartrate/peraceticacid or the like as the oxidizing agent.

3-1) Preparation Process of Sulfonyl Compound (1c)

The sulfonyl compound (1c) in the present invention can be prepared, asdescribed below, by oxidizing the sulfide compound (1a) or sulfinylcompound (1b) with an oxidizing agent in a solvent.

(wherein, R¹ to R⁴ each has the same meaning as described above).

The reaction temperature is usually from −20° C. to 150° C., preferablyfrom 0° C. to 100° C. and the reaction time usually ranges from 0.1 hourto 7 days, preferably from 1 hour to 5 days.

Examples of the solvent include alcohol solvents, ether solvents,halogen solvents, aromatic solvents, carboxylic acid solvents, nitrilesolvents, amide solvents, ketone solvents, sulfoxide solvents and water.Two or more of them may be used as a mixture. Of these, methylenechloride, chloroform, methanol, ethanol, acetic acid, water and the likeare preferred.

Examples of the oxidizing agent include hydrogen peroxide, hydrogenperoxide-transition metal catalyst (such as ammonium molybdate or iron(III) chloride), organic peracid compounds (such as peracetic acid andmetachloroperbenzoic acid), metaperiodates (such as sodiummetaperiodate), potassium peroxysulfate, permanganates (such aspotassium permanganate), sodium perborate, halogens, N-halogen compounds(such as N-chlorosuccinimide and N-bromosuccinimide), hydroperoxides(such as t-butylhydroperoxide), iodobenzene diacetate, iodobenzenedichloride, hypochlorites (such as sodium hypochlorite or t-butylhypochlorite), singlet oxygen, ozone, selenium oxide, and seleninicacid. The preferred example of the reaction conditions include reactionof the sulfide compound (1a) with from 2 to 5 equivalents of anoxidizing agent (such as meta-chloroperbenzoic acid, sodium periodate,hydrogen peroxide or hydrogen peroxide-ammonium molybdate) in methylenechloride, tetrahydrofuran-water or methanol at from 0 to 100° C. forfrom about 1 hour to 5 days.

3-2) Preparation Process of Sulfonyl Compound (1c)

The sulfonyl compound (1c) can also be prepared by the below-describedprocess.

[wherein, Y¹ represents an eliminating group or a hydroxyl group and R¹to R⁴ each has the same meaning as described above].

The sulfonyl compounds (1c) having a variety of groups as R² can each beprepared by reacting the sulfonyl compound (1d), which can be preparedin a known method or in accordance with the known method, with anelectrophilic reagent (R²—Y¹) in the presence of a base.

Described specifically, the compound (1d) is reacted with an equivalentto excess amount of R²—Y¹ in the presence of an equivalent to excessamount of a base. The reaction temperature usually ranges from −78° C.to 200° C. and the reaction time usually ranges from 0.5 hour to 1 day.

As the solvent, ether solvents, halogen solvents, aromatic solvents,nitrile solvents, amide solvents and the like can be used either singlyor in combination. Of these, tetrahydrofuran, dimethoxyethane, diethylether, dimethylformamide, toluene and the like are preferred.

Examples of the eliminating group represented by Y¹ include halogenatoms (such as chlorine, bromine and iodine), C₁₋₆ alkylsulfonyloxygroups which may be halogenated (such as methanesulfonyloxy,ethanesulfonyloxy and trifluoromethanesulfonyloxy) and C₆₋₁₀ aromatichydrocarbon sulfonyloxy groups which may have a substituent. Examples ofthe substituent for the aromatic hydrocarbon sulfonyloxy group include 1to 3 halogen atoms, C₁₋₆ alkyl groups which may be halogenated and C₁₋₆alkoxy groups. Specific of the C₆₋₁₀ aromatic hydrocarbon sulfonyloxygroups which may have a substituent include benzenesulfonyloxy,p-toluenesulfonyloxy, 1-naphthalenesulfonyloxy and2-naphthalensulfonyloxy.

Examples of the base include alkyl lithiums (such as n-butyl lithium,s-butyl lithium and t-butyl lithium), hydrides of an alkali metal oralkaline earth metal (such as lithium hydride, sodium hydride, potassiumhydride and calcium hydride), amides of an alkali metal or alkalineearth metal (such as lithium amide, sodium amide, lithiumdiisopropylamide, lithium dicyclohexylamide, lithiumhexamethyldisilazide, sodium hexamethyldisilazide and potassiumhexamethyldisilazide), lower alkoxides of an alkali metal or alkalineearth metal (such as sodium methoxide, sodium ethoxide and potassiumt-butoxide), hydroxides of an alkali metal, alkaline earth metal orsilver (such as silver hydroxide, sodium hydroxide, potassium hydroxide,lithium hydroxide and barium hydroxide), carbonates of an alkali metal,alkaline earth metal or silver (sodium carbonate, potassium carbonate,cesium carbonate and silver carbonate), bicarbonates of an alkali metal(such as sodium bicarbonate and potassium bicarbonate), and silveroxide.

3-3) Preparation Process of Sulfonyl Compound (1c)

The sulfonyl compound (1c) in the present invention can be also beprepared, as described below, by reacting the compound (3) with analkali metal, alkaline earth metal or tetrabutylammonium salt of asulfinic acid represented by R³—SO₂ ⁻M⁺ (5).

(wherein, Y represents an eliminating group, M⁺ represents a metal ion,and R¹ to R⁴ each has the same meaning as described above).

Described specifically, the compound (3) is reacted with an equivalentto excess amount of sulfinic acid or salt thereof (5) in a solvent. Thereaction temperature usually ranges from −20° C. to 200° C., preferablyfrom room temperature to 100° C. A reaction temperature higher than theabove-described range is sometimes preferred, depending on the kind ofthe compound (3) or sulfinate (5). The reaction in a sealed tube issometimes preferred. The reaction time usually ranges from 0.5 hour to 3days, preferably from 0.5 hour to 1 day.

Examples of the solvent include alcohol solvents, ether solvents,halogen solvents, aromatic solvents, nitrile solvents, amide solvents,ketone solvents, sulfoxide solvents and water. These solvents may beused as a mixture. Of these, butanol, dimethoxyethane,N-methylpyrrolidone, dimethylformamide and the like are preferred.

In the above-described preparation processes of the compound (1)according to the present invention, a substituent such as nitrogen atom,hydroxyl group or carboxyl group sometimes needs protection and in thiscase, a generally known protecting group which can be removed as neededcan be employed. The protecting group can be eliminated by the generalorganic chemical method if necessary.

One or more substituents in R¹ to R⁴ of the sulfide compound (1a),sulfinyl compound (1b) and sulfonyl compound (1c) prepared in any one ofthe above-described processes can be subjected to further structureconversion. For example, when the compound has, in any one of R¹ to R⁴,a substituent substituted with a 1,3-dioxolan-2-yl group, it can beconverted into a compound substituted with a formyl group by thehydrolysis in a known manner. When the compound has, in any one of R¹ toR⁴, a substituent substituted with a bromo group, it can be convertedinto a compound substituted with a formyl group in a known manner. Theformyl group can be converted into, in a known manner, a carboxylicacid, substituted or unsubstituted aminomethyl group, hydroxymethylgroup, 2-(alkoxycarbonyl)ethenyl group or the like. Moreover, thehydroxyl group portion of the hydroxymethyl group can be converted intoester, carbonate, carbamate, halogen, nitrile, sulfonate or the likegroup in a known manner. Furthermore, these groups can be converted intoan alkoxy, amine, amide, carboxylic acid, sulfide or the like group. The2-(alkoxycarbonyl)ethenyl group can be converted into a 2-carboxyethylgroup or the like in a known manner. Not only the above-described groupsbut also various functional groups besides a hydroxyl group can besubjected to such conversion. Conversion can be carried out based on theknown technique. Described specifically, when R² represents a2-chloro-4-pyridyl group, by reacting the compound with an amine such asalkylamine, dialkylamine, benzylamine, pyrrolidine, piperidine ormorpholine, a pyridine derivative having the chloro group at the2-position substituted with the above-described amine can be prepared.In this case, use of 3,4-dimethoxybenzylamine yields a3,4-dimethoxybenzylaminopyridine, and treatment of the resultingcompound with trifluoroacetic acid or cerium diammonium nitrate yields a2-aminopyridine derivative. Moreover, treatment of the 2-aminopyridinederivative with methanesulfonyl chloride in the presence of pyridineconverts it into a 2-methanesulfonylaminopyridine derivative. In theseconversion steps, reagents, solvents and reaction conditions known tothose skilled in the art may be used.

The compounds (1) of the present invention prepared by theabove-described process can be introduced into their salts or solvatesby the ordinary process.

The compounds (1) of the present invention strongly inhibit productionor secretion of β-amyloid protein so that they are useful as amedicament for preventing or treating diseases resulting from abnormalproduction or secretion of β-amyloid protein such as Alzheimer diseaseand Down syndrome or the other diseases associated with amyloiddeposition.

When the compound of the present invention is used as a medicament forhuman, the adult daily dose ranges from 1 mg to 1 g, preferably from 10mg to 300 mg. When it is administered to animals, the dose varies,depending on the purpose of administration (treatment or prevention),kind or size of the animal to be treated, the kind or degree of bacteriawith which the animal has been infected, but daily dose usually rangesfrom 0.1 mg to 200 mg, preferably from 0.5 mg to 100 mg per kg of theweight of the animal. The daily dose is administered once a day or fromtwo to four portions a day. The daily dose may exceed theabove-described amount, if necessary.

The pharmaceutical composition containing the compound of the presentinvention can be formulated into a desired form selected in accordancewith the administration route by using various ordinarily employedpreparation processes. Examples of the form of the pharmaceuticalcomposition having the compound of the present invention as a mainingredient include oral administrable preparations such as tablets,powders, granules, capsules, liquids, syrups, elixirs, oily or aqueoussuspensions.

Injections may contain therein a stabilizer, antiseptic, solubilizingagent or the like. It is also possible to reconstitute a solidpreparation, which has been obtained by filling a vessel with a solutionwhich may contain such an agent and then lyophilizing it, upon use. Anamount to be administered once may be filled in one vessel or an amountto be administered plural times may be filled in one vessel.

Examples of the preparation for external use include liquids,suspensions, emulsions, ointments, gels, creams, lotions, sprays andplasters.

The solid preparation contains, together with the compound of thepresent invention, pharmaceutically acceptable additives. It can beprepared by mixing the compound of the present invention with additivesselected from fillers, extenders, binders, disintegrants, solubilizingpromoters, humectants and lubricants as needed.

Examples of the liquid preparations include solutions, suspensions andemulsions. They may contain a suspending agent or emulsifier as anadditive.

EXAMPLES

The present invention will hereinafter be described more specifically byexamples. It should however be borne in mind that the scope of thepresent invention is not limited to the below-described examples. Allthe compounds obtained by the below-described examples belong to eitherone of E type or Z type unless specifically indicated.

Referential Example 12-[(4-Chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene

Process 1:

1) At 0° C., 4-chlorobenzenethiol (5.45 g, 38.2 mmol),triphenylphosphine (11.1 g, 41.6 mmol) and diisopropyl azodicarboxylate(8.16 ml, 41.6 mmol) were sequentially added to a tetrahydrofuran (150ml) solution of 2,5-difluorobenzyl alcohol (5.00 g, 34.7 mmol). Thereaction mixture was stirred at room temperature for 4 days, followed byconcentration. The residue thus obtained was purified by silica gelcolumn chromatography (1% ethyl acetate-hexane) to give2-[(4-chlorophenyl)thiomethyl]-1,4-difluorobenzene (2.68 g, 29%) as acolorless oil.

¹H-NMR(400 MHz,CDCl₃)δ: 4.04(2H,s), 6.85-7.00(3H,m), 7.23(4H,s).

2) After addition of 3-chloroperbenzoic acid (225 mg, 1.30 mmol) to amethylene chloride (5 ml) solution of2-[(4-chlorophenyl)thiomethyl]-1,4-difluorobenzene (271 mg, 1.00 mmol)at 0° C., the resulting mixture was stirred at room temperature for 15hours. The reaction mixture was diluted with methylene chloride, washedwith a saturated aqueous solution of potassium bicarbonate and brine,dried (over MgSO₄), and concentrated. The residue thus obtained wasdissolved in methylene chloride (5 ml). After cooling to 0° C.,3-chloroperbenzoic acid (450 mg, 2.60 mmol) was added and the resultingmixture was stirred at room temperature for 15 hours. The reactionmixture was diluted with methylene chloride. The diluted solution waswashed with a saturated aqueous solution of potassium bicarbonate andbrine, dried (over MgSO₄), and concentrated. The residue thus obtainedwas purified by silica gel column chromatography (9%-ethylacetate-hexane) to give the title compound (210 mg, 69%) as a colorlesssolid substance.

¹H-NMR(400 MHz,CDCl₃)δ: 4.36(2H,s), 6.91(1H,td,J=9.0,4.4 Hz),6.99-7.06(1H,m), 7.11(1H,ddd,J=8.3,5.6,3.2 Hz), 7.45(2H,d,J=8.8 Hz),7.62(2H,d,J=8.8 Hz).

MS(m/z): 303(M⁺+H)

Process 2:

1) After addition of potassium carbonate (4.00 g, 29.0 mmol) and2-bromomethyl-1,4-difluorobenzene (5.00 g, 24.2 mmol) to anN,N-dimethylformamide (120 ml) solution of 4-chlorobenzenethiol (3.86 g,26.6 mmol), the resulting mixture was stirred at room temperature for 3hours. To the reaction mixture were added saturated ammonium chloride(50 ml) and water (20 ml), followed by extraction with diethyl ether.The extracts were combined, washed with water and brine, dried (overMgSO₄), and concentrated. The residue thus obtained was purified bysilica gel column chromatography (1% ethyl acetate-hexane) to give2-[(4-chlorophenyl)thiomethyl]-1,4-difluorobenzene (6.41 g, 98%) as acolorless oil.

2) At 0° C., H₂O (16.4 ml), 30% H₂O₂ (16.4 ml, 145 mmol) andhexaammonium heptamolybdate tetrahydrate (425 mg, 0.344 mmol) were addedto a methanol (100 ml) solution of2-[(4-chlorophenyl)thiomethyl]-1,4-difluorobenzene (6.54 g, 24.1 mmol).The resulting mixture was stirred for 1 hour, followed by stirring atroom temperature for 15 hours. The solid thus precipitated was collectedby filtration and the filtrate was concentrated to about half of itsamount. The resulting aqueous solution was extracted with methylenechloride. The solid obtained previously was dissolved in the extract.The resulting solution was washed sequentially with water and brine,dried (over MgSO₄) and concentration. The residue thus obtained wasrecrystallized from hexane to give the title compound (6.34 g, 87%) ascolorless needle crystals.

Process 3: To a butanol (200 ml) suspension of sodium4-chlorobenzenesulfinate (19.0 g, 95.5 mmol) was added2-bromomethyl-1,4-difluorobenzene (12.3 ml, 95.5 mmol). The resultingmixture was heated under reflux for 5 hours. The solid thus precipitatedwas collected by filtration, and dissolved in methylene chloride. Theresulting solution was washed with brine, dried (over MgSO₄). Afterconcentration, the solid thus obtained was recrystallized from hexane togive the title compound (12.3 g, 43%) as colorless needle crystals.

Referential Example 2 4-(4-Chlorophenylsulfonylmethyl)pyridine

A 1-propanol (50 ml) solution of 4-chloromethylpyridine hydrochloride(1.26 g, 7.65 mmol), sodium 4-chlorobenzenesulfinate (1.52 g, 7.65 mmol)and potassium acetate (1.50 g, 15.3 mmol) was stirred under heating at70° C. for 8 hours. The reaction mixture was cooled to room temperatureand then concentrated under reduced pressure. The residue thus obtainedwas caused to pass through a short column (silica gel, ethyl acetate)and the eluate was concentrated under reduced pressure. The residue thusobtained was subjected to silica gel column chromatography, and thefraction obtained from the hexane:ethyl acetate (=2:3) eluate wasconcentrated under reduced pressure to give the title compound (1.26 g,62%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 4.29(2H,s), 7.06(2H,d,J=6.1 Hz), 7.47(2H,d,J=8.8Hz), 7.59(2H,d,J=8.5 Hz), 8.57(2H,d,J=6.1 Hz).

MS(m/z): 268(M⁺+H)

Referential Example 3 2-[(2,5-Difluorophenyl)-hydroxymethyl]pyridine

A hexane solution (1.53M, 3.92 ml, 0.6 mmol) of n-butyl lithium wasadded dropwise to a tetrahydrofuran (10 ml) solution of 2-bromopyridine(572 μl, 6 mmol) under an argon atmosphere at −78° C., followed bystirring for 30 minutes. To the resulting brown solution was addeddropwise 2,5-difluorobenzaldehyde (655 μl, 6 mmol) and the temperatureof the reaction mixture was gradually raised to room temperature. To thereaction mixture was added water. The resulting mixture was thenextracted with ethyl acetate. After the solvent was dried, the residueobtained by concentration under reduced pressure was purified bypurification by silica gel chromatography to give the title compound(120 mg, 9%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 5.45(1H,br), 6.08(1H,s), 6.87-7.15(3H,m),7.2-7.3(2H,m), 7.65(1H,m), 8.56(1H,m).

mp: 65 to 66° C.

Referential Example 42-[Chloro-(2,5-difluorophenyl)methyl]-3-methylpyridine hydrochloride

Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol)of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran(2.0 ml) solution of 2-bromo-3-methylpyridine (510 mg, 3 mmol) under icecooling. The resulting mixture was stirred at room temperature for 60minutes. To the resulting brown solution, 2,5-difluorobenzaldehyde (328μl, 3 mmol) was added dropwise under ice cooling. The temperature of thereaction mixture was then raised to room temperature gradually. Afteraddition of a saturated aqueous solution of ammonium chloride, theresulting mixture was extracted with ethyl acetate. After the solventwas dried, the residue obtained by concentration under reduced pressurewas purified by silica gel chromatography (hexane:ethyl acetate=8:1) togive a mixture containing the title compound. Thionyl chloride (2.0 ml)and one drop of dimethylformamide were added to the mixture. Theresulting mixture was stirred at room temperature for 14 hours. Excessthionyl chloride was distilled off under reduced pressure to yield awhite precipitate. The resulting precipitate was triturated with hexaneand diethyl ether to give the title compound (101 mg, 12%).

¹H-NMR(400 MHz,CDCl₃)δ: 2.37(3H,s), 6.95-7.10(2H,m), 7.28(1H,s),7.7-7.8(2H,m), 8.11(1H,d,J=6.3 Hz), 8.72 (1H, d, J=4.9 Hz).

mp: 118 to 119° C.

MSm/z: 254 (M⁺+H).

Referential Example 52-[(2,5-Difluorophenyl)-hydroxymethyl]-5-methylpyridine

Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol)of isopropylmagnesium chloride was added dropwise to tetrahydrofuran (2ml) solution of 2-bromo-5-methylpyridine (510 mg, 3 mmol) under icecooling. The resulting mixture was stirred at room temperature for 60minutes. To the resulting brown solution was added dropwise2,5-difluorobenzaldehyde (328 μl, 3 mmol) under ice cooling and then,the temperature of the reaction mixture was raised to room temperaturegradually. A saturated aqueous solution of ammonium chloride was addedto the reaction mixture and then, the mixture was extracted with ethylacetate. After drying the solvent, the residue obtained by concentrationunder reduced pressure was purified by silica gel chromatography(hexane:ethyl acetate=5:1) to give the title compound (130 mg, 18%) asan oil.

¹H-NMR(400 MHz,CDCl₃)δ: 2.31(3H,s), 5.38(1H,br), 6.04(1H,s),6.83-7.18(4H,m), 7.44(1H,dd,J=2.0,8.0 Hz), 8.37(1H,m).

MSm/z: 236(M⁺+H).

Referential Example 62-[(2,5-Difluorophenyl)-hydroxymethyl]-4-methylpyridine

Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol)of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran(2 ml) solution of 2-bromo-4-methylpyridine (334 μl, 3 mmol) under icecooling. The resulting mixture was stirred at room temperature for 60minutes. To the resulting brown solution was added dropwise2,5-difluorobenzaldehyde (328 μl, 3 mmol) under ice cooling. Thetemperature of the resulting mixture was gradually raised to roomtemperature. After addition of a saturated aqueous solution of ammoniumchloride, the resulting mixture was extracted with ethyl acetate. Thesolvent was then dried. The residue obtained by concentration underreduced pressure was purified by silica gel chromatography (hexane:ethylacetate=5:1) to give the title compound (456 mg, 65%) as needlecrystals.

¹H-NMR(400 MHz,CDCl₃)δ: 2.30(3H,s), 5.48(1H,br-s), 6.02(1H,s),6.83-7.13(5H,m), 8.38(1H,m).

mp: 105 to 106° C.

MSm/z: 236(M⁺+H).

Referential Example 7 2-Bromo-3-methoxypyridine

Under a nitrogen atmosphere, sodium hydride 60% in oil (605 mg, 15.1mmol) was added in portions to methanol (10 ml) under ice cooling.Twenty minutes later, a dimethylformamide (20 ml) solution of2-bromo-3-hydroxypyridine (2.5 g, 14.4 mmol) was added. From theresulting mixture, methanol was distilled off under reduced pressure. Tothe residue was added methyl iodide (0.94 ml, 15.1 mmol), followed bystirring at room temperature for 3 hours. After the reaction mixture wasconcentrated to dryness, water (50 ml) and ether (50 ml) were added tothe concentrate. The organic layer was separated and washed with asaturated aqueous solution of sodium bicarbonate and brine. The extractwas dried over anhydrous magnesium sulfate, and concentrated underreduced pressure to remove the solvent. The residue was purified bysilica gel chromatography (hexane:ethyl acetate=8:1) to give the titlecompound (1.51 g, 56%) as colorless needle crystals.

¹H-NMR(400 MHz,CDCl₃)δ: 3.90(3H,s), 7.12(1H,m), 7.21(1H,dd,J=4.8,8.0Hz), 7.97(1H,m).

mp: 34° C.

Referential Example 8 3-Allyloxy-2-bromopyridine

Synthesis was performed in a similar manner to that employed for thesynthesis of 2-bromo-3-methoxypyridine to give the title compound (2.35g, 76%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 4.62(2H,m), 5.33(1H,dd,J=1.2,10.4 Hz),5.47(1H,dd,J=1.2,17.6 Hz), 6.06(1H,m), 7.11(1H,dd,J=1.2 Hz,8.0 Hz),7.18(1H,dd,J=4.8,8.0 Hz), 7.98(1H,m).

MSm/z: 215(M⁺+H).

Referential Example 92-[(2,5-Difluorophenyl)-hydroxymethyl]-3-methoxypyridine

Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol)of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran(2 ml) solution of 2-bromo-3-methoxypyridine (564 mg, 3 mmol) under icecooling. The reaction mixture was then stirred at room temperature for60 minutes. To the resulting brown solution, 2,5-difluorobenzaldehyde(328 μl, 3 mmol) was added dropwise under ice cooling. The temperatureof the reaction mixture was gradually raised to room temperature. Afteraddition of a saturated aqueous solution of ammonium chloride, theresulting mixture was extracted with ethyl acetate. After the solventwas dried, needle crystals obtained by concentration under reducedpressure were triturated with hexane to give the title compound (660 mg,88%).

¹H-NMR(400 MHz,CDCl₃)δ: 3.71(3H,s), 5.56(1H,br,J=6.0 Hz),6.16(1H,d,J=6.0 Hz), 6.75-7.00(3H,m), 7.14(1H,m), 7.26(1H,m),8.18(1H,m).

mp: 94 to 95° C.

MSm/z: 252(M⁺+H).

Referential Example 103-Allyloxy-2-[(2,5-difluorophenyl)-hydroxymethyl]pyridine

Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol)of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran(2 ml) solution of the 3-allyloxy-2-bromopyridine (642 mg, 3 mmol)obtained in Referential Example 8 under ice cooling. The resultingmixture was stirred at room temperature for 60 minutes. To the resultingbrown solution was added dropwise 2,5-difluorobenzaldehyde (328 μl, 3mmol) under ice cooling. The temperature of the reaction mixture wasgradually raised to room temperature. A saturated aqueous solution ofammonium chloride was added to the reaction mixture, followed byextraction with ethyl acetate. The solvent was then dried and theresidue obtained by concentration under reduced pressure was purified bysilica gel chromatography (hexane:ethyl acetate=4:1) to give the titlecompound (375 mg, 45%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 4.38(1H,m), 4.44(1H,m), 5.16(1H,m), 5.18(1H,m),5.61(1H,br,J=6.4 Hz), 5.78(1H,m), 6.17(1H,d,J=6.0 Hz), 6.73-6.96(3H,m),7.10(1H,m), 7.22(1H,m), 8.19(1H,m).

MSm/z: 278(M⁺+H).

Referential Example 11 3-[(2,5-Difluorophenyl)-hydroxymethyl]pyridine

Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol)of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran(2 ml) solution of 3-bromopyridine (286 μl, 3 mmol) under ice cooling.The resulting mixture was stirred at room temperature for 60 minutes. Tothe resulting brown solution thus obtained was added dropwise2,5-difluorobenzaldehyde (328 μl, 3 mmol) under ice cooling. Thetemperature of the reaction mixture was gradually raised to roomtemperature. A saturated aqueous solution of ammonium chloride was addedto the reaction mixture, followed by extraction with ethyl acetate. Thesolvent was then dried. The residue remaining after concentration underreduced pressure was purified by silica gel chromatography (hexane:ethylacetate=1:1) to give the title compound (296 mg, 45%) as needlecrystals.

¹H-NMR(400 MHz,CDCl₃)δ: 3.76(1H,br), 6.10(1H,s), 6.88-6.98(2H,m),7.20-7.30(2H,m), 7.70(1H,m), 8.42(1H,d,J=4.8 Hz), 8.53(1H,m).

mp: 79 to 80° C.

Referential Example 12 5-[(2,5-Difluorophenyl)-hydroxymethyl]pyrimidine

In a similar manner to Referential Example 11, the title compound (117mg, 18%) as an oil by using 5-bromopyrimidine.

¹H-NMR(400 MHz,CDCl₃)δ: 6.12(1H,s), 6.90-7.02(2H,m), 7.26(1H,m),8.70(2H,s), 9.04(1H,s).

MSm/z: 205(M⁺—OH).

Referential Example 132-[(t-Butoxycarbonyloxy)-(2,5-difluorophenyl)methyl]-1-methyl-1H-benzimidazole

An acetonitrile (3 ml) solution of 2,5-difluorobenzaldehyde (164 μl, 1.5mmol), 1-methylbenzimidazole (132 mg, 1 mmol) and di-t-butyl dicarbonate(252 μl, 1.1 mmol) was stirred at room temperature for 20 hours. Theprecipitate thus formed was collected by filtration and then trituratedwith hexane to give the title compound (310 mg, 83%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 1.45(9H,s), 3.86(3H,s), 6.9-7.0(2H,m),7.12(1H,s), 7.22-7.35(3H,m), 7.45(1H,m), 7.77(1H,d,J=8.0 Hz).

mp: 163 to 164° C.

MSm/z: 375(M⁺+H).

Referential Example 142-[(t-Butoxycarbonyloxy)-(2,5-difluorophenyl)methyl]-1-methyl-5-chloro-1H-imidazole

An acetonitrile (6 ml) solution of 2,5-difluorobenzaldehyde (327 μl, 3mmol), 5-chloro-1-methylimidazole (187 μg, 2 mmol) and di-t-butyldicarbonate (504 μl, 2.2 mmol) was stirred at room temperature for 20hours. The precipitate thus formed was collected by filtration, followedby trituration with hexane to give the title compound (472 mg, 66%) as awhite solid.

¹H-NMR(400 MHz,CDCl₃)δ: 1.48(9H,s), 3.67(3H,s), 6.88-7.1(4H,m),7.39(1H,m).

mp: 125 to 126° C.

MSm/z: 359(M⁺+H).

Referential Example 15 2-[(2,5-Difluorophenyl)-hydroxymethyl]thiazole

To a tetrahydrofuran (10 ml) solution of 2-bromothiazole (180 μg, 2mmol) was added dropwise a hexane solution (1.57M, 1.40 ml, 2.2 mmol) ofn-butyl lithium at −78° C., followed by stirring for 10 minutes. Then,2,5-difluorobenzaldehyde (238 μl, 2.2 mmol) was added and thetemperature of the resulting mixture was raised gradually to 0° C. understirring. An aqueous solution of ammonium chloride was added toterminate the reaction and ether was added to the reaction mixture. Theether layer was washed with water and brine, and then dried overanhydrous magnesium sulfate. After filtration, the solution wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography (hexane:ethyl acetate=1:1) to give the title compound(358 mg, 79%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 3.77(1H,d,J=4.0 Hz), 6.33(1H,d,J=4.0 Hz),6.95-7.10(2H,m), 7.24(1H,m), 7.34(1H,d,J=3.6 Hz), 7.75(1H,d,J=3.6 Hz),

MSm/z: 228(M⁺+H).

Referential Example 162-[(t-Butoxycarbonyloxy)-(2,5-difluorophenyl)methyl]-1-(4-methoxyphenyl)-1H-imidazole

An acetonitrile (6 ml) solution of 2,5-difluorobenzaldehyde (327 μl, 3mmol), 1-(4-methoxyphenyl)imidazole (348 mg, 2 mmol) and di-t-butyldicarbonate (504 μl, 2.2 mmol) was stirred at room temperature for 20hours. The reaction mixture was concentrated and then the residue waspurified by silica gel chromatography (hexane:ethyl acetate=5:1 to 1:1)to give the title compound (774 mg, 93%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 1.40(9H,s), 3.86(3H,s), 6.76(1H,s),6.90-7.00(4H,m), 7.02(1H,s), 7.11(1H,s), 7.26(2H,m), 7.33(1H,m).

MSm/z: 417(M⁺+H).

Referential Example 17 5-Chloro-2-pyridinethiol

Thiourea (152 mg, 2.00 mmol) was added to an ethanol (4 ml) solution of2,5-dichloropyridine (296 mg, 2.00 mmol). The mixture was then heatedunder reflux for 18 hours. After the reaction mixture was cooled to roomtemperature, a water (1 ml) solution of potassium hydroxide (198 mg,3.00 mmol) was added and the mixture was heated under reflux for 3hours. The reaction mixture was cooled to room temperature. Water wasthen added and the mixture was washed with dichloromethane. The waterlayer was acidified with acetic acid, followed by extraction withdichloromethane. The organic layer was dried over anhydrous sodiumsulfate and then filtered. After filtration, the filtrate wasconcentrated under reduced pressure. The solid thus obtained was washedwith diethyl ether and collected by filtration to give the titlecompound (83 mg, 0.57 mmol, 29%) as a yellow powder.

¹H-NMR(400 MHz,CDCl₃)δ: 7.35(1H,dd,J=9.3,2.4 Hz), 7.46(1H,d,J=9.3 Hz),7.64(1H,d,J=2.4 Hz).

MSm/z: 146(M⁺+H).

Referential Example 18 2,5-Difluorophenyl-4-pyridylmethanol

A tetrahydrofuran (30 ml) solution of 1-bromo-2,5-difluorobenzene (1.08ml, 9.60 mmol) was stirred at −78° C., followed by the addition of ahexane solution (7.32 ml, 11.5 mmol) of n-butyl lithium. To the reactionmixture was added a tetrahydrofuran (10 ml) solution of4-pyridinecarboxyaldehyde (0.764 ml, 8.00 mmol) at −78° C. The resultingmixture was stirred at the same temperature for 30 minutes. After thetemperature of the reaction mixture was raised to room temperature,diethyl ether was added thereto. The resulting mixture was washed with asaturated aqueous solution of sodium bicarbonate. The organic layer wasdried over anhydrous sodium sulfate and then filtered. The filtrate wasconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel chromatography. The fraction obtained fromthe hexane:ethyl acetate=7:3 eluate was concentrated under reducedpressure. The solid thus obtained was washed with diisopropyl ether andthen collected by filtration to give the title compound (1.15 g, 5.20mmol, 65%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 4.25(1H,brs), 6.09(1H,s), 6.89-7.05(2H,m),7.14-7.23(1H,m), 7.34(2H,d,J=5.4 Hz), 8.44(2H,d,J=5.4 Hz)

Referential Example 19 Tetrahydrothiopyran-4-ol

Tetrahydrothiopyran-4-one (5.00 g, 43.0 mmol) was dissolved in methanol(100 ml). After sodium borohydride (1.6 g, 42.3 mmol) was added to theresulting solution under ice cooling, the resulting mixture was stirredat room temperature for 14 hours. Water (50 ml) was added to the residueobtained by concentrating the reaction mixture under reduced pressure.The liquid property of the resulting mixture was then made weakly acidicwith 1N hydrochloric acid, followed by extraction with diethyl ether.The extract was washed sequentially with 1N hydrochloric acid, asaturated aqueous solution of sodium bicarbonate, and brine. The organiclayer was dried over anhydrous magnesium sulfate. After filtration, thefiltrate was concentrated under reduced pressure to give the titlecompound (4.40 g, 37.2 mmol, 87%) as a pale yellowish brown solid.

¹H-NMR(400 MHz,CDCl₃)δ: 1.47(1H,brs), 1.64-1.80(2H,m), 2.10-2.24(2H,m),2.55-2.70(2H,m), 2.73-2.88(2H,m), 3.60-3.75(1H,m).

MSm/z: 119(M⁺+H).

Referential Example 20 5-Dibromomethyl-2-(2,5-difluorobenzoyl)pyridine(Compound A) and 5-bromomethyl-2-(2,5-difluorobenzoyl)pyridine (CompoundB)

Under heating and refluxing, N-bromosuccinimide (17.0 g, 95.7 mmol) anda catalytic amount of 2,2′-azobis(2-methylpropionitrile) were added to acarbon tetrachloride (100 ml) solution of the2-[(2,5-difluorophenyl)-hydroxymethyl]-5-methylpyridine (7.50 g, 31.9mmol) obtained in Referential Example 5. The resulting mixture wasstirred at reflux for 24 hours. The reaction mixture was cooled to roomtemperature and the precipitate thus formed was filtered off. Theprecipitate was added to an aqueous solution of sodium thiosulfate,followed by extraction with chloroform. The extract was washed with asaturated aqueous solution of sodium bicarbonate and brine, and thendried over sodium sulfate. The residue obtained by concentrating thesolution under reduced pressure was purified by silica gelchromatography (hexane:ethyl acetate=10:1) to give the title compound A(3.91 g, 31%) and the title compound B (3.34 g, 34%), each as an oil.

Compound A

¹H-NMR(400 MHz,CDCl₃)δ: 6.70(1H,s), 7.12(1H,m), 7.24(1H,m), 7.39(1H,m),8.12(1H,d,J=8.4 Hz), 8.19(1H,dd,J=2.0,8.4 Hz), 8.77(1H,d,J=2.0 Hz).

MSm/z: 392(M⁺+H).

Compound B

¹H-NMR(400 MHz,CDCl₃)δ: 4.52(2H,s), 7.12(1H,m), 7.21(1H,m), 7.39(1H,m),7.94(1H,dd,J=2.0,8.0 Hz), 8.08(1H,d,J=8.0 Hz), 8.67(1H,d,J=2.0 Hz).

MSm/z: 313(M⁺+H).

Referential Example 21[6-(2,5-Difluorophenylcarbonyl)pyridin-3-yl]methyl acetate

Under heating and refluxing, N-bromosuccinimide (6.0 g, 33.6 mmol) and acatalytic amount of 2,2′-azobis(2-methylpropionitrile) were added to acarbon tetrachloride (60 ml) solution of the2-[(2,5-difluorophenyl)-hydroxymethyl]-5-methylpyridine (2.64 g, 11.2mmol) obtained in Referential Example 5. The resulting mixture was thenstirred. After refluxing for 7 hours, the reaction mixture was cooled toroom temperature and added to an aqueous solution of sodium thiosulfate.The resulting mixture was extracted with ether. The extract was washedwith saturated water and brine, and then dried over sodium sulfate. Theresidue obtained by concentrating the solution under reduced pressurewas dissolved in toluene. The resulting solution was concentrated again.

The residue thus obtained was dissolved in N,N-dimethylformamide (20ml). To the resulting solution was added sodium acetate (4.59 g, 56mmol) and the mixture was stirred at 70° C. for 17 hours. After cooling,the reaction mixture was dissolved in ethyl acetate (100 ml). Thesolution was washed with water and brine, dried over anhydrous magnesiumsulfate and then concentrated under reduced pressure. The residue thusobtained was purified by silica gel chromatography (hexane:ethylacetate=5:1) to yield the title compound (600 mg, 18%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 2.12(3H,s), 5.19(2H,s), 7.10(1H,m), 7.19(1H,m),7.37(1H,s), 7.88(1H,dd,J=2.4,8.0 Hz), 8.07(1H,d,J=8.0 Hz),8.62(1H,d,J=2.4 Hz).

MSm/z: 292(M⁺+H).

Referential Example 222-[(2,5-Difluorophenyl)-hydroxymethyl]-5-(1,3-dioxolan-2-yl)pyridine

To a pyridine solution (60 ml) of the5-dibromomethyl-2-(2,5-difluorobenzoyl)pyridine (Compound A) (3.91 g, 10mmol) obtained in Referential Example 20 was added ethylene glycol (6.2g, 100 mmol). While heating at 90° C., the resulting mixture was stirredfor 17 hours. The reaction mixture was concentrated under reducedpressure. The residue thus obtained was dissolved in ether (200 ml). Theresulting solution was washed with water, a saturated aqueous solutionof sodium bicarbonate and brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue thus obtained wasdissolved in ethanol (60 ml). To the resulting solution was added sodiumborohydride (190 mg, 5 mmol) under ice cooling. The resulting mixturewas stirred at room temperature for 1 hour. After the addition of water,the mixture was extracted with ethyl acetate. The extract was washedwith brine, dried over anhydrous magnesium sulfate, and thenconcentrated under reduced pressure. The residue thus obtained waspurified by silica gel chromatography (hexane:ethyl acetate=5:1 to 1:1)to give the title compound (1.52 g, 52%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 4.0-4.2(4H,m), 5.84(1H,s), 6.10(1H,s),6.91(1H,m), 6.99(1H,m), 7.09(1H,m), 7.26(1H,d,J=8.0 Hz),7.76(1H,dd,J=2.0,8.0 Hz), 8.64(1H,d,J=2.0 Hz).

MSm/z: 294(M⁺+H).

Referential Example 233-Chloro-4-[(2,5-difluorophenyl)-hydroxymethyl]pyridine

To a tetrahydrofuran solution (14 ml) of diisopropylamine (1.4 ml, 10mmol) was added n-butyl lithium (6.3 ml, a 1.59M hexane solution) at−78° C. After the resulting mixture was stirred for 10 minutes,3-chloropyridine (1.13 g, 10 mmol) was added thereto. Thirty minuteslater, 2,5-difluorobenzaldehyde (1.09 ml, 10 mmol) was added and thetemperature of the resulting mixture was raised gradually to 0° C.Stirring was conducted for further 10 minutes. After addition of anaqueous solution of ammonium chloride, the resulting mixture was dilutedwith ethyl acetate (80 ml). The organic layer was separated, washed withbrine and then dried. After filtration, the precipitate obtained byconcentrating the resulting solution under reduced pressure wastriturated with ethanol to give the title compound (1.33 g, 52%).

¹H-NMR(400 MHz,CDCl₃)δ: 4.87(1H,br), 6.26(1H,s), 6.90-7.02(3H,m),7.58(1H,d,J=4.8 Hz), 8.47(1H,s), 8.48(1H,d,J=4.8 Hz).

mp: 169 to 170° C.

MSm/z: 255(M⁺).

Referential Example 242,5-Dichloro-4-[(2,5-difluorophenyl)-hydroxymethyl]pyridine

To a tetrahydrofuran solution (14 ml) of diisopropylamine (1.4 ml, 10mmol) was added n-butyl lithium (6.3 ml, a 1.59M hexane solution) at−78° C. After stirring for 10 minutes, 2,5-dichloropyridine (1.48 g, 10mmol) was added to the reaction mixture. Thirty minutes later,2,5-difluorobenzaldehyde (1.09 ml, 10 mmol) was added and thetemperature of the resulting mixture was raised gradually to 0° C.Stirring was conducted for further 10 minutes. After addition of anaqueous solution of ammonium chloride, the resulting mixture was dilutedwith ethyl acetate (80 ml). The organic layer was separated, washed withbrine and then dried. After filtration, the precipitate obtained byconcentrating the filtrate under reduced pressure was triturated withethanol to give the title compound (1.93 g, 67%).

¹H-NMR(400 MHz,CDCl₃)δ: 2.64(1H,d,J=4.0 Hz), 6.28(1H,d,J=4.0 Hz),6.89(1H,m), 7.02(2H,m), 7.64(1H,s), 8.30(1H,s).

mp: 160 to 161° C.

MSm/z: 289(M⁺).

Referential Example 25 (3,6-Dichloropyridin-2-yl)(pyridin-4-yl)methanol

Under stirring at −78° C., t-butyl lithium (a 1.51M pentane solution:4.6 ml) was added dropwise to an ether (20 ml) solution of2,5-dichloropyridine (1.02 g, 6.89 mmol). After stirring at −78° C. for2 hours, pyridine-4-carbaldehyde (0.65 ml, 6.89 mmol) was added to thereaction mixture. The resulting mixture was stirred at −78° C. for 1hour. Water was then added to the reaction mixture. The temperature ofthe resulting mixture was raised to room temperature. The mixture wasextracted with methylene chloride. The extract was then dried overanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue thus obtained wassubjected to silica gel column chromatography. The fraction obtainedfrom the methanol:methylene chloride (=1:50) eluate was concentratedunder reduced pressure. The solid thus obtained was washed with etherand then collected by filtration to give the title compound (819 mg,3.21 mmol, 47%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 4.64(1H,brd,J=6.3 Hz), 6.00(1H,brd,J=6.3 Hz),7.27(1H,d,J=8.6 Hz), 7.31(2H,d,J=5.8 Hz), 7.67(1H,d,J=8.6 Hz),8.57(2H,d,J=5.8 Hz).

MS (m/z): 254 (M+).

Referential Example 26 O-ethyl S-(6-chloro-3-pyridyl)dithiocarbonate

5-Amino-2-chloropyridine (643 mg, 3.00 mmol) was dissolved in 1Nhydrochloric acid (10 ml). A water (1 ml) solution of sodium nitrite(207 mg, 3.00 mmol) was added dropwise at −5° C. The reaction mixturewas stirred at 60° C. for 30 minutes and then, at the same temperature,a water (1 ml) solution of potassium O-ethyl dithiocarbonate (481 mg,3.00 mmol) was added dropwise. After the reaction mixture was stirred at80° C. for 1 hour, the reaction mixture was cooled to room temperature.Ethyl acetate was added and the resulting mixture was washed with asaturated aqueous solution of sodium bicarbonate. The organic layer wasdried over anhydrous sodium sulfate and then filtered. The filtrate wasconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate=49:1 eluate was concentratedunder reduced pressure to give the title compound (148 mg, 0.63 mmol,21%) as a yellow oil.

¹H-NMR(400 MHz,CDCl₃)δ: 1.37(3H,t,J=7.1 Hz), 4.63(2H,t,J=7.1 Hz),7.41(1H,d,J=8.3 Hz), 7.76(1H,dd,J=8.3,2.4 Hz), 8.45(1H,d,J=2.4 Hz).

MSm/z: 234(M⁺+H).

Referential Example 27 (2,6-Dichloro-5-fluoropyridin-3-yl)methanol

Under ice cooling, ethyl chloroformate (1.32 ml, 13.8 mmol) was added toa toluene (60 ml) solution of 2,6-dichloro-5-fluoronicotinic acid (2.76g, 13.1 mmol) and triethylamine (1.92 ml, 13.8 mmol). After stirring atroom temperature for 1 hour, the reaction mixture was concentrated underreduced pressure.

The residue was dissolved in tetrahydrofuran (30 ml). The resultingsolution was added dropwise, at −78° C., to a tetrahydrofuran (20 ml)suspension of lithium aluminum hydride (524 mg, 13.8 mmol). Thetemperature of the reaction mixture was raised to 0° C. A 1N aqueoussodium hydroxide solution (3.25 ml) was added dropwise thereto. Theprecipitate was filtered off through Celite and the filtrate wasconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel chromatography. The fraction obtained fromthe hexane:ethyl acetate=9:1 eluate was concentrated under reducedpressure to give the title compound (1.93 g, 9.85 mmol, 75%) as anorange solid.

¹H-NMR(400 MHz,CDCl₃)δ: 2.18(1H,brs), 4.77(2H,s), 7.77(1H,d,J=7.8 Hz).

mp: 65 to 67° C.

Referential Example 283-(t-Butyldiphenylsilyloxymethyl)-5-fluoropyridine

To an ethanol (650 ml) solution of the(2,6-dichloro-5-fluoropyridin-3-yl)methanol (18.9 g, 96.2 mmol) obtainedin Referential Example 27 and triethylamine (32.2 ml, 231 mmol) wasadded a 10% palladium-carbon catalyst (3.20 g). The resulting mixturewas stirred for 7 hours under a hydrogen atmosphere. The catalyst wasfiltered off through Celite, and then, the filtrate was concentratedunder reduced pressure. To the residue thus obtained was added asaturated aqueous solution of sodium bicarbonate, followed by extractionwith chloroform. The organic layer was dried over anhydrous sodiumsulfate and then filtered. The filtrate was concentrated under reducedpressure.

The residue thus obtained was dissolved in dichloromethane (600 ml). Tothe resulting solution were sequentially added triethylamine (14.8 ml,106 mmol), t-butylchlorodiphenylsilane (25.0 ml, 96.3 mmol) and4-dimethylaminopyridine (1.18 g, 9.63 mmol). The resulting mixture wasstirred at room temperature for 14 hours. The reaction mixture waswashed with a saturated aqueous solution of sodium bicarbonate. Theorganic layer was dried over anhydrous sodium sulfate and then filtered.The filtrate was concentrated under reduced pressure. The residue thusobtained was subjected to flash silica gel chromatography, and Thefraction obtained from the hexane:ethyl acetate=19:1 eluate wasconcentrated under reduced pressure to give the title compound (30.0 g,81.9 mmol, 85%) as a colorless oil.

¹H-NMR(400 MHz,CDCl₃)δ: 1.10(9H,s), 4.78(2H,s), 7.36-7.49(7H,m),7.63-7.70(4H,m), 8.32(1H,s), 8.36(1H,d,J=2.4 Hz).

MSm/z: 366(M⁺+H).

Referential Example 29[5-(t-Butyldiphenylsilyloxymethyl)-3-fluoropyridin-2-yl](2,5-difluorophenyl)methanol

At −78° C., a hexane solution (30.0 ml, 46.8 mmol) of n-butyl lithiumand N,N,N,N′N′-tetramethylethylenediamine (7.06 ml, 46.8 mmol) wereadded sequentially to diethyl ether (250 ml). After stirring at −20° C.for 30 minutes, the reaction mixture was cooled to −78° C., and adiethyl ether (50 ml) solution of3-(t-butyldiphenylsilyloxymethyl)-5-fluoropyridine (15.5 g, 42.5 mmol)was added thereto. The resulting mixture was stirred at the sametemperature for 30 minutes. To the reaction mixture was added2,5-difluorobenzaldehyde (6.04 g, 42.5 mmol). The resulting mixture wasstirred for 2 hours. Water and then, a saturated aqueous solution ofsodium bicarbonate were added to the reaction mixture. The resultingmixture was extracted with diethyl ether. The organic layer was driedover anhydrous sodium sulfate and then, filtered. The filtrate wasconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel chromatography. The fraction obtained fromthe hexane:ethyl acetate=9:1 eluate was concentrated under reducedpressure to give the title compound (17.0 g, 33.5 mmol, 79%) as acolorless oil.

¹H-NMR(400 MHz,CDCl₃)δ: 1.10(9H,s), 4.78(2H,s), 5.12(1H,d,J=6.6 Hz),6.22(1H,d,J=6.6 Hz), 6.87-7.04(3H,m), 7.33-7.48(7H,m), 7.61-7.70(4H,m),8.32(1H,s).

MSm/z: 508(M⁺+H).

Referential Example 30(2,5-Difluorophenyl)(3-fluoro-5-hydroxymethylpyridin-2-yl)methanol

To a tetrahydrofuran (7 ml) solution of[5-(t-butyldiphenylsilyloxymethyl)-3-fluoropyridin-2-yl](2,5-difluorophenyl)methanol(853 mg, 1.68 mmol) was added a tetrahydrofuran solution (1.04 ml, 1.04mmol) of tetrabutylammonium fluoride. The mixture was stirred at roomtemperature for 5 hours. After the reaction mixture was concentratedunder reduced pressure, the residue thus obtained was dissolved in ethylacetate. The resulting solution was washed with a saturated aqueoussolution of sodium bicarbonate. The organic layer was dried overanhydrous sodium sulfate and then, filtered. The filtrate wasconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel chromatography. The fraction obtained fromthe hexane:ethyl acetate=1:1 eluate was concentrated under reducedpressure to give the title compound (413 mg, 1.53 mmol, 91%) as a whitesolid.

¹H-NMR(400 MHz,CDCl₃)δ: 1.91(1H,t,J=5.4 Hz), 4.79(2H,d,J=5.4 Hz),5.16(1H,d,J=6.6 Hz), 6.23(1H,d,J=6.6 Hz), 6.75-7.04(3H,m),7.46(1H,d,J=9.8 Hz), 8.41(1H,s).

mp: 94 to 96° C.

MSm/z: 270(M⁺+H).

Referential Example 316-(2,5-Difluorophenyl)hydroxymethyl-5-fluoronicotinamide

To an acetone (9 ml) solution of the(2,5-difluorophenyl)(3-fluoro-5-hydroxymethylpyridin-2-yl)methanol (406mg, 1.51 mmol) obtained in Referential Example 30 was added a water (9ml) solution of potassium permanganate (795 mg, 7.03 mmol) and theresulting mixture was heated under reflux for 4 hours. The precipitatewas filtered off through Celite. The filtrate was acidified with 1Nhydrochloric acid, followed by extraction with dichloromethane. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure. The residue thusobtained was washed with a mixed solvent of hexane and dichloromethane,and then collected by filtration to give a white solid (367 mg).

To an N,N-dimethylformamide (8 ml) solution of the resulting solid (240mg) were added 1H-benzotriazol-1-yloxytripyrrolidinophosphoniumhexafluorophosphate (666 mg, 1.28 mmol), benzotriazol-1-ol (173 mg, 1.28mmol), N-ethyldiisopropylamine (0.595 ml, 3.41 mmol) and ammoniumchloride (91 mg, 1.71 mmol) and the resulting mixture was stirred atroom temperature for 9 hours. To the reaction mixture was added ethylacetate. The resulting mixture was washed sequentially with a saturatedaqueous solution of ammonium chloride, a saturated aqueous solution ofsodium bicarbonate, and brine. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentratedunder reduced pressure. The residue thus obtained was subjected to flashsilica gel chromatography, and the fraction obtained from thehexane:ethyl acetate=1:4 eluate was concentrated under reduced pressure.

The residue thus obtained was dissolved in ethanol (8 ml). At 0° C.,sodium borohydride (30 mg, 0.79 mmol) was added to the resultingsolution. After stirring at room temperature for 1 hour, water was addedto the reaction mixture. The resulting mixture was extracted withdichloromethane. The organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated under reducedpressure. The residue thus obtained was subjected to flash silica gelchromatography. The fraction obtained from the ethyl acetate eluate wasconcentrated under reduced pressure to give the title compound (118 mg,0.42 mmol, 42%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 4.97(1H,d,J=6.6 Hz), 6.27(1H,d,J=6.6 Hz),6.91-7.06(3H,m), 7.87(1H,dd,J=9.4,1.6 Hz), 8.81(1H,s).

mp: 162 to 164° C.

MSm/z: 283(M⁺+H).

Referential Example 322-[(2,5-Difluorophenyl)hydroxymethyl]-6-(1,3-dioxolan-2-yl)pyridine

Under an argon atmosphere, a tetrahydrofuran solution (2.0M, 12.4 ml,24.8 mmol) of isopropylmagnesium chloride was added dropwise to atetrahydrofuran (20 ml) solution of2-bromo-6-(1,3-dioxolan-2-yl)pyridine (2.7 ml, 24.8 mmol) under icecooling. The reaction mixture was stirred at room temperature for 3hours. To the resulting brown solution was added dropwise2,5-difluorobenzaldehyde (2.7 ml, 24.8 mmol) under ice cooling. Thetemperature of the reaction mixture was raised gradually to roomtemperature and then, stirring was conducted for 16 hours. After asaturated aqueous solution of ammonium chloride was added, the resultingmixture was extracted with ethyl acetate. The extract was washedsequentially with water and brine. The organic layer thus obtained wasdried over magnesium sulfate and concentrated under reduced pressure.The residue was subjected to silica gel column chromatography. Thefraction obtained from the hexane:ethyl acetate=4:1 eluate wasconcentrated under reduced pressure to give the title compound (2.90 g,9.89 mmol, 40%) as a colorless oil.

¹H-NMR(400 MHz,CDCl₃)δ: 4.09-4.21(4H,m), 5.43(1H,d,J=4.4 Hz),5.90(1H,s), 6.11(1H,d,J=4.4 Hz), 6.87-6.95(1H,m), 6.99-7.05(1H,m),7.10-7.15(1H,m), 7.23(1H,d,J=7.8 Hz), 7.48(1H,d,J=7.8 Hz),7.72(1H,t,J=7.8 Hz).

MSm/z: 294 (M⁺+H).

Referential Example 331-[3-(t-Butyldimethylsilyloxy)propyl]piperidin-2-one

At 0° C., sodium hydride (60% in oil, 2.22 g, 55.6 mmol) was added inportions to a tetrahydrofuran solution (200 ml) of piperidin-2-one (5.00g, 50.5 mmol). The reaction mixture was then stirred at room temperaturefor 3 hours. After addition of (3-bromopropoxy)-t-butyldimethylsilane(14.1 ml, 60.6 mmol) and N,N-dimethylformamide (20 ml) to the reactionmixture, the resulting mixture was stirred at room temperature for 4days. Water was added to the reaction mixture, followed by extractionwith ethyl acetate. The extract was washed with water and brine, driedover magnesium sulfate and concentrated. The residue thus obtained wassubjected to silica gel column chromatography. The fraction obtainedfrom the hexane:ethyl acetate=2:1 eluate was concentrated to give thetitle compound (6.44 g, 23.8 mmol, 47%) as a colorless oil.

¹H-NMR(400 MHz,CDCl₃)δ: 0.05(6H,s), 0.89(9H,s), 1.74-1.85(6H,m),2.36(2H,t,J=6.0 Hz), 3.27-3.32(2H,m), 3.39-3.43(2H,m), 3.65(2H,t,J=6.3Hz).

MSm/z: 272(M⁺+H).

Referential Example 343-Bromo-1-[3-(t-butyldimethylsilyloxy)propyl]piperidin-2-one

Under an argon atmosphere, t-butyl lithium (a 1.50M pentane solution,1.40 ml, 2.10 mmol) was added dropwise to a tetrahydrofuran solution (5ml) of 1-[3-(t-butyldimethylsilyloxy)propyl]piperidin-2-one (542 mg,2.00 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 15minutes. After a tetrahydrofuran solution (5 ml) of tetrabutylammoniumtribromide (1.16 g, 2.40 mmol) was added to the reaction mixture, thetemperature of the resulting mixture was gradually raised to −40° C.under stirring. Water was added to the reaction mixture at −40° C. andthen, the temperature of the mixture was raised to room temperature. Thereaction mixture was extracted with ethyl acetate. The extract waswashed with water and brine, dried over magnesium sulfate andconcentrated. The residue thus obtained was subjected to flash silicagel column chromatography. The fraction obtained from the hexane:ethylacetate=2:3 eluate was concentrated to give the title compound (72.8 mg,0.208 mmol, 10%) as a colorless oil.

¹H-NMR(400 MHz,CDCl₃)δ: 0.05(6H,s), 0.89(9H,s), 1.74-1.88(3H,m),2.18-2.32(3H,m), 3.28-3.48(4H,m), 3.65(2H,t,J=6.1 Hz), 4.53-4.57(1H,m).

MSm/z: 350(M⁺+H).

Example 12-[[(4-Chlorophenyl)sulfonyl](cyclohexyl)methyl]-1,4-difluorobenzene

The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (240 mg,0.793 mmol) obtained in Referential Example 1 was dissolved in toluene(20 ml). After addition of cyclohexanol (0.11 ml, 1.0 mmol) andcyanomethylenetri-n-butylphosphorane (250 mg, 1.0 mmol), the resultingmixture was heated under reflux for 14 hours under an argon atmosphere.The reaction mixture was allowed to cool and then, cyclohexanol (0.22ml, 2.1 mmol) and cyanomethylenetri-n-butylphosphorane (500 mg, 2.08mmol) were added thereto. Under an argon atmosphere, the resultingmixture was heated under reflux for 14 hours. The reaction mixture wasallowed to cool and concentrated under reduced pressure. The residuethus obtained was purified by silica gel chromatography (hexane:ethylacetate=30:1) to give a white solid. The white solid was washed withhexane to give the title compound (188 mg, 62%) as a white powder.

Melting point: 107 to 109° C.

¹H-NMR(400 MHz,CDCl₃)δ: 0.92-1.08(1H,m), 1.08-1.22(1H,m),1.22-1.50(3H,m), 1.60-1.75(3H,m), 1.75-1.88(1H,m), 2.37(1H,brd,J=12.5Hz), 2.48-2.62(1H,m), 4.44(1H,d,J=7.6 Hz), 6.68-6.80(1H,m),6.86-6.95(1H,m), 7.30(2H,dm,J=8.6 Hz), 7.38-7.52(1H,m), 7.49(2H,dm,J=8.6Hz).

Elemental Analysis for C₁₉H₁₉ClF₂O₂S: Calculated: C, 59.29; H, 4.98; Cl,9.21; F, 9.87; S, 8.33. Found: C, 59.11; H, 4.93; Cl, 9.18; F, 9.82; S,8.49.

Example 2 4-[(4-Chlorophenylsulfonyl)(cyclopentyl)methyl]pyridine

A toluene (5 ml) solution of the4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained inReferential Example 2, cyclopentanol (49 μl, 0.538 mmol) andcyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) was heatedunder reflux for 3 days under an argon atmosphere. After cooling to roomtemperature, cyclopentanol (49 μl, 0.538 mmol) andcyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) were added tothe reaction mixture. Under an argon atmosphere, the reaction mixturewas heated under reflux for 22 hours. The reaction mixture was cooled toroom temperature and then, concentrated under reduced pressure. Theresidue thus obtained was subjected to flash silica gel columnchromatography, and the fraction obtained from the hexane:ethyl acetate(=2:1) eluate was concentrated under reduced pressure to give the titlecompound (77 mg, 88%) as a white solid. The solid thus obtained waswashed with hexane-ether and filtered to give the title compound as awhite powder.

Melting point: 133 to 135° C.

¹H-NMR(400 MHz,CDCl₃)δ: 0.92-1.08(1H,m), 1.44-1.83(6H,m),2.33-2.45(1H,m), 2.78-2.90(1H,m), 3.88(1H,d,J=10.3 Hz), 7.03(2H,d,J=5.1Hz), 7.32(2H,d,J=8.6 Hz), 7.43(2H,d,J=8.6 Hz), 8.46(2H,d,J=5.6 Hz)

Elemental Analysis for C₁₇H₁₈ClNO₂S: Calculated: C, 60.80; H, 5.40; Cl,11.56; N, 4.17; S, 9.55. Found: C, 60.76; H, 5.44; Cl, 10.68; N, 4.20;S, 9.61.

Example 34-[(4-Chlorophenylsulfonyl)(tetrahydropyran-4-yl)methyl]pyridine

A toluene (5 ml) solution of the4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained inReferential Example 2, tetrahydropyran-4-ol (51 μl, 0.538 mmol) andcyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) was heatedunder reflux for 3 days under an argon atmosphere. After the reactionmixture was cooled to room temperature, tetrahydropyran-4-ol (51 μl,0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol)were added thereto. The mixture was heated under reflux for 22 hoursunder an argon atmosphere. After cooling to room temperature, thereaction mixture was concentrated under reduced pressure. The residuethus obtained was subjected to flash silica gel column chromatography.The fraction obtained from the hexane:ethyl acetate (=1:2) eluate wasconcentrated under reduced pressure to give the title compound (65 mg,71%) a white solid. The solid thus obtained was washed withhexane-ether, and filtered to give the title compound as a white powder.

Melting point: 208 to 209° C.

¹H-NMR(400 MHz,CDCl₃)δ: 1.22-1.42(2H,m), 1.60-1.75(1H,m),2.30-2.40(1H,m), 2.78-3.01(1H,m), 3.41(1H,td,J=11.7,2.4 Hz),3.51(1H,td,J=11.9,2.0 Hz), 3.80-3.93(1H,m), 3.87(1H,d,J=8.6 Hz),3.98-4.06(1H,m), 7.00-7.12(2H,m), 7.30(2H,d,J=8.8 Hz), 7.43(2H,d,J=8.6Hz), 8.47(2H,d,J=5.4 Hz).

MS (m/z): 352 (M⁺+H).

Example 44-[(1-Benzylpiperidin-4-yl)(4-chlorophenylsulfonyl)methyl]pyridine

A toluene (5 ml) solution of the4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained inReferential Example 2,1-benzylpiperidin-4-ol (103 mg, 0.538 mmol) andcyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) was heatedunder reflux for 3 days under an argon atmosphere. After cooling to roomtemperature, 1-benzylpiperidin-4-ol (103 mg, 0.538 mmol) andcyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) were added tothe reaction mixture. Under an argon atmosphere, the resulting mixturewas heated under reflux for 22 hours. After cooling to room temperature,the reaction mixture was concentrated under reduced pressure. Theresidue thus obtained was subjected to flash silica gel columnchromatography. The fraction obtained from the methanol:methylenechloride (=1:10) eluate was concentrated under reduced pressure. Theresidue thus obtained was purified by high performance liquidchromatography (by using a mixed solvent system ofwater/acetonitrile/formic acid) to give the title compound (40 mg, 35%)as an amorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ:1.21-1.37(2H,m), 1.49-1.70(1H,m),1.92-2.01(1H,m), 2.03-2.14(1H,m), 2.25-2.35(1H,m), 2.52-2.65(1H,m),2.79-2.85(1H,m), 2.90-3.00(1H,m), 3.47(2H,s), 3.86(1H,d,J=8.1 Hz),7.02-7.12(2H,m), 7.20-7.38(7H,m), 7.43(2H,d,J=8.5 Hz), 8.45(2H,d,J=5.4Hz).

HRMS (FAB): as C₂₄H₂₆O₂N₂ClS(M⁺+H)

Calculated: 441.1404. Found: 441.1387.

Example 54-[(4-Chlorophenylsulfonyl)(1-methylpiperidin-4-yl)methyl]pyridine

A toluene (5 ml) solution of the4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained inReferential Example 2, 1-methylpiperidin-4-ol (62 μl, 0.538 mmol) andcyanomethylenetri-n-butylphosphorane (62 μl, 0.538 mol) was heated underreflux for 3 days under an argon atmosphere. After cooling to roomtemperature, 1-methylpiperidin-4-ol (62 μl, 0.538 mmol) andcyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) were added tothe reaction mixture. Under an argon atmosphere, the resulting mixturewas heated under reflux for 22 hours. After cooling to room temperature,the reaction mixture was concentrated under reduced pressure. Theresidue thus obtained was subjected to silica gel column chromatography.The fraction obtained from the methanol:methylene chloride (=1:50)eluate was concentrated under reduced pressure. The residue thusobtained was purified by high performance liquid chromatography (using amixed solvent system of water/acetonitrile/formic acid) to give thetitle compound (31 mg, 33%) as a white solid. The solid thus obtainedwas washed with hexane-ether and filtered to give the title compound asa white powder.

Melting point: 176 to 177° C.

¹H-NMR(400 MHz,CDCl₃)δ: 1.22-1.38(2H,m), 1.50-1.68(1H,m),1.88-1.99(1H,m), 2.00-2.10(1H,m), 2.25(3H,s), 2.30-2.40(1H,m),2.50-2.63(1H,m), 2.74-2.83(1H,m), 2.89-2.95(1H,m), 3.86(1H,d,J=8.3 Hz),7.08(2H,d,J=4.6 Hz), 7.30(2H,d,J=8.6 Hz), 7.44(2H,d,J=8.6 Hz),8.46(2H,d,J=5.6 Hz).

Elemental Analysis for C₁₈H₂₁ClN₂O₂S: Calculated: C, 59.25; H, 5.80; Cl,9.72; N, 7.68; S, 8.79. Found: C, 59.00; H, 5.76; Cl, 9.75; N, 7.61; S,8.77.

Example 6 2-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]pyridine

The 2-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (88 mg, 0.40 mmol)obtained in Referential Example 3 was dissolved in thionyl chloride (2.0ml). To the resulting solution was added a catalytic amount ofdimethylformamide, followed by stirring for 15 hours. The reactionmixture was concentrated under reduced pressure. To the residue wasadded dioxane, and the resulting mixture was concentrated further. Theresidue was dissolved in dimethylformamide (5 ml). To the resultingsolution were added 4-chlorobenzenethiol (79 mg, 0.55 mmol) andpotassium carbonate (226 mg, 1.64 mmol) under a nitrogen atmosphere, andthe mixture was stirred at 50° C. for 1 hour. After the reaction mixturewas cooled to room temperature, diethyl ether (50 ml) was added thereto.The resulting mixture was washed with water and brine. The organic layerwas dried over magnesium sulfate, and concentrated under reducedpressure. The residue was subjected to silica gel chromatography(hexane:ethyl acetate=10:1) to give the title compound (128 mg, 92%) asan oil.

¹H-NMR(400 MHz,CDCl₃)δ: 5.89(1H,s), 6.80-7.27(7H,m), 7.38(1H,d,J=7.6Hz), 7.48(1H,m), 7.65(1H,m), 8.63(1H,m).

MSm/z: 348(M⁺+H).

Example 72-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-3-methylpyridine

To a dimethylformamide (5 ml) solution of the2-[chloro-(2,5-difluorophenyl)methyl]-3-methylpyridine hydrochloride (94mg, 0.32 mmol) obtained in Referential Example 4 were added4-chlorobenzenethiol (70 mg, 0.49 mmol) and potassium carbonate (265 mg,1.92 mmol) under a nitrogen atmosphere. The resulting mixture wasstirred at 50° C. for 1 hour. After the reaction mixture was cooled toroom temperature, diethyl ether (50 ml) was added thereto. The resultingmixture was washed with water and brine. The organic layer was driedover magnesium sulfate and concentrated under reduced pressure. Theresidue thus obtained was subjected to silica gel chromatography(hexane:ethyl acetate=10:1) to give the title compound (103 mg, 89%) asan oil.

¹H-NMR(400 MHz,CDCl₃)δ: 2.21(3H,s), 5.87(1H,s), 6.77(1H,m),7.00-7.19(5H,m), 7.36(1H,m), 7.45(1H,m), 8.45(1H,dd,J=1.2,4.8 Hz).

MSm/z: 362(M⁺+H).

Example 82-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-4-methylpyridine

After the 2-[(2,5-difluorophenyl)-hydroxymethyl]-4-methylpyridine (235mg, 0.53 mmol) obtained in Referential Example 6 was dissolved inthionyl chloride (2.0 ml), a catalytic amount of dimethylformamide wasadded to the resulting solution. The resulting mixture was stirred for16 hours. The reaction mixture was concentrated under reduced pressure.To the residue was added dioxane, followed by further concentration. Theresidue thus obtained was dissolved in dimethylformamide (10 ml). To theresulting solution were added 4-chlorobenzenethiol (217 mg, 1.5 mmol)and potassium carbonate (828 mg, 6.0 mmol) under a nitrogen atmosphere.The resulting mixture was stirred at 50° C. for 1 hour. After thereaction mixture was cooled to room temperature, diethyl ether (50 ml)was added thereto. The resulting mixture was washed with water andbrine. The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure. The residue thus obtained wassubjected to silica gel chromatography (hexane:ethyl acetate=10:1) togive the title compound (290 mg, 80%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 2.31(3H,s), 5.82(1H,s), 6.80-7.0(3H,m),7.15(2H,d,J=8.8 Hz), 7.16(1H,m), 7.21(2H,d,J=8.8 Hz), 7.45(1H,m),8.45(1H,d,J=5.6 Hz).

MSm/z: 362(M⁺+H).

Example 92-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-3-methoxypyridine

After the 2-[(2,5-difluorophenyl)-hydroxymethyl]-3-methoxypyridine (251mg, 1.0 mmol) obtained in Referential Example 9 was dissolved in thionylchloride (2.0 ml), a catalytic amount of dimethylformamide was added tothe resulting solution. The resulting mixture was stirred for 16 hours.The reaction mixture was concentrated under reduced pressure. To theresidue was added dioxane, followed by further concentration. Theresidue thus obtained was dissolved in dimethylformamide (10 ml). To theresulting solution were added 4-chlorobenzenethiol (289 mg, 2.0 mmol)and potassium carbonate (1.10 g, 8.0 mmol) under a nitrogen atmosphere.The resulting mixture was stirred at 50° C. for 1 hour. After thereaction mixture was cooled to room temperature, diethyl ether (50 ml)was added thereto. The resulting mixture was washed with water andbrine. The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure. The residue was subjected to silicagel chromatography (hexane:ethyl acetate=10:1) to give the titlecompound (256 mg, 58%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 3.77(3H,s), 6.25(1H,s), 6.82(2H,m),7.15(2H,d,J=8.4 Hz), 7.10-7.20(2H,m), 7.25(2H,d,J=8.8 Hz), 7.52(1H,m),8.24(1H,m).

MSm/z: 378(M⁺+H).

Example 103-Allyloxy-2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]pyridine

The 3-allyloxy-2-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (370 mg,1.33 mmol) obtained in Referential Example 10 was dissolved in thionylchloride (2.0 ml). To the resulting solution was added a catalyticamount of dimethylformamide. The resulting mixture was stirred for 16hours. The reaction mixture was concentrated under reduced pressure.Dioxane was added to the residue, followed by further concentration. Theresidue thus obtained was dissolved in dimethylformamide (10 ml). To theresulting solution were added 4-chlorobenzenethiol (217 mg, 1.5 mmol)and potassium carbonate (828 mg, 6.0 mmol) under a nitrogen atmosphere.The resulting mixture was stirred at 50° C. for 1 hour. After thereaction mixture was cooled to room temperature, diethyl ether (50 ml)was added thereto. The resulting mixture was washed with water andbrine. The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure. The residue was subjected to silicagel chromatography (hexane:ethyl acetate=10:1) to give the titlecompound (256 mg, 68%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 4.46(2H,m), 5.24(1H,d,J=10.6 Hz), 5.28(1H,d,J=17.2 Hz), 5.90(1H,m), 6.29(1H,d,J=1.2 Hz), 6.82(2H,m),7.15(2H,d,J=8.4 Hz), 7.06-7.20(2H,m), 7.24(2H,d,J=8.4 Hz), 7.50(1H,m),8.24(1H,m).

MSm/z: 404(M⁺+H).

Example 11 3-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]pyridine

The 3-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (87 mg, 0.39 mmol)obtained in Referential Example 11 was dissolved in thionyl chloride(1.0 ml). A catalytic amount of dimethylformamide was added to theresulting solution and the resulting mixture was stirred for 14 hours.The reaction mixture was concentrated under reduced pressure. To theresidue was added dioxane and the resulting mixture was concentratedfurther. The residue thus obtained was dissolved in dimethylformamide (5ml), followed by the addition of 4-chlorobenzenethiol (84 mg, 0.58 mmol)and potassium carbonate (323 mg, 2.34 mmol) under a nitrogen atmosphere.The resulting mixture was stirred at 50° C. for 1 hour. After thereaction mixture was cooled to room temperature, diethyl ether (50 ml)was added thereto. The resulting mixture was washed with water andbrine. The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure. The residue thus obtained wassubjected to silica gel chromatography (hexane:ethyl acetate=1:1) togive the title compound (131 mg, 96%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 5.73(1H,s), 6.84-6.96(2H,m), 7.18(2H,m),7.19(2H,m), 7.15-7.22(2H,m), 7.71(1H,m), 8.49(1H,dd,J=1.6,4.8 Hz),8.58(1H,d,J=2.0 Hz).

MSm/z: 348(M⁺+H).

Example 125-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]pyrimidine

The 5-[(2,5-difluorophenyl)-hydroxymethyl]pyrimidine (111 mg, 0.5 mmol)obtained in Referential Example 12 was dissolved in thionyl chloride(1.0 ml). A catalytic amount of dimethylformamide was added and theresulting mixture was stirred for 16 hours. The reaction mixture wasconcentrated under reduced pressure. To the residue was added dioxane,and the resulting mixture was concentrated further. The residue wasdissolved in dimethylformamide (5 ml), followed by the addition of4-chlorobenzenethiol (108 mg, 0.75 mmol) and potassium carbonate (414mg, 3.0 mmol) under a nitrogen atmosphere. The resulting mixture wasstirred at 50° C. for 1 hour. After the reaction mixture was cooled toroom temperature, diethyl ether (50 ml) was added thereto. The resultingmixture was washed with water and brine. The organic layer was driedover magnesium sulfate and concentrated under reduced pressure. Theresidue was subjected to silica gel chromatography (hexane:ethylacetate=4:1) to give a mixture (202 mg) of the title compound and anunidentified compound as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 5.66(1H,s), 6.96(2H,m), 7.17-7.34(5H,d),8.70(2H,s), 9.09(1H,s).

MSm/z: 349(M⁺+H).

Example 132-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]pyridine

To a methanol (12 ml) solution of the2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]pyridine (120 mg,0.345 mmol) obtained in Example 6 was added hexaammonium heptamolybdatetetrahydrate (80 mg). To the resulting mixture was added 30% aqueoushydrogen peroxide (6 ml), followed by stirring for 24 hours. Theprecipitate thus formed was collected by filtration and recrystallizedfrom ethanol to give the title compound (96 mg, 73%) as colorless needlecrystals.

¹H-NMR(400 MHz,CDCl₃)δ: 5.93(1H,s), 6.87-7.00(2H,m), 7.28(1H,m),7.37(2H,d,J=8.8 Hz), 7.53(2H,d,J=8.8 Hz), 7.60(1H,d,J=8.0 Hz),7.71(1H,m), 8.00(1H,m), 8.59(1H,m).

mp: 171 to 172° C.

MSm/z: 380(M⁺+H).

Elemental Analysis for C₁₈H₁₂ClF₂NO₂S: Calculated: C, 56.92; H, 3.18; N,3.69; S, 8.44; Cl, 9.33; F, 10.00. Found: C, 56.76; H, 3.19; N, 3.77; S,8.55; Cl, 9.27; F, 10.02.

Example 142-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]-3-methylpyridine

In a similar manner to Example 13, the title compound (35 mg, 35%) ascolorless needle crystals by synthesizing using the2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-3-methylpyridineobtained in Example 7 and purifying by silica gel chromatography(hexane:ethyl acetate=5:1).

¹H-NMR(400 MHz,CDCl₃)δ: 2.36(3H,s), 6.18(1H,s), 6.89-7.02(2H,m),7.17(1H,m), 7.37(2H,d,J=8.4 Hz), 7.46(1H,d,J=7.2 Hz), 7.53(2H,d,J=8.4Hz), 8.06(1H,m), 8.53 (1H,d, J=4.0 Hz)

mp: 142 to 143° C.

Elemental Analysis for C₁₉H₁₄ClF₂NO₂S: Calculated: C, 57.94; H, 3.58; N,3.56; S, 8.12; Cl, 9.00; F, 9.65. Found: C, 58.03; H, 3.66; N, 3.78; S,8.12; Cl, 9.13; F, 9.59.

Example 152-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]-5-methylpyridine

1)2-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-5-methylpyridine

The 2-[(2,5-difluorophenyl)-hydroxymethyl]-5-methylpyridine (125 mg,0.53 mmol) obtained in Referential Example 5 was dissolved in thionylchloride (1.0 ml). To the resulting solution was added a catalyticamount of dimethylformamide. The resulting mixture was stirred for 14hours. The reaction mixture was concentrated under reduced pressure.Dioxane was added to the residue, followed by further concentration. Theresidue was dissolved in dimethylformamide (5 ml). To the resultingsolution were added 4-chlorobenzenethiol (115 mg, 0.80 mmol) andpotassium carbonate (438 mg, 3.18 mmol) under a nitrogen atmosphere. Theresulting mixture was stirred at 50° C. for 1 hour. After the reactionmixture was cooled to room temperature, diethyl ether (50 ml) was addedthereto. The resulting mixture was washed with water and brine. Theorganic layer was dried over magnesium sulfate and concentrated underreduced pressure. The residue was subjected to silica gel chromatography(hexane:ethyl acetate=10:1) to give the title compound (120 mg, 66%) asan oil.

¹H-NMR(400 MHz,CDCl₃)δ: 2.29(3H,s), 5.83(1H,s), 6.80-6.93(2H,m),7.16(2H,m), 7.20(2H,m), 7.28(1H,m), 7.43(1H,m), 8.41 (1H,d,J=0.8 Hz).

MSm/z: 362(M⁺+H).

2)2-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]-5-methylpyridine

In a similar manner to Example 13, the title compound (91 mg, 73%) ascolorless needle crystals by the synthesis using the2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-5-methylpyridineobtained by the above reaction.

¹H-NMR(400 MHz,CDCl₃)δ: 2.33(3H,s), 5.89(1H,s), 6.88-7.01(2H,m),7.37(2H,d,J=8.8 Hz), 7.48-7.56(2H,m), 7.53(2H,d,J=8.8 Hz), 7.99(1H,m),8.42(1H,s).

mp: 159 to 160° C.

Elemental Analysis for C₁₉H₁₄ClF₂NO₂S: Calculated: C, 57.94; H, 3.58; N,3.56; S, 8.12; Cl, 9.00; F, 9.56. Found: C, 57.88; H, 3.61; N, 3.68; S,8.27; Cl, 9.11; F, 9.70.

Example 162-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]-4-methylpyridine

In a similar manner to Example 13, the title compound (140 mg, 95%) ascolorless needle crystals by the synthesis using the2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-4-methylpyridineobtained in Example 8 and purification by silica gel chromatography(hexane:ethyl acetate=3:1).

¹H-NMR(400 MHz,CDCl₃)δ: 2.36(3H,s), 5.88(1H,s), 6.88-7.02(2H,m),7.09(1H,d,J=5.2 Hz), 7.37(2H,d,J=8.8 Hz), 7.41(1H,m), 7.52(2H,d,J=8.8Hz), 7.97(1H,m), 8.43(1H,d,J=5.2 Hz).

mp: 116 to 117° C.

Elemental Analysis for C₁₉H₁₄ClF₂NO₂S: Calculated: C, 57.94; H, 3.58; N,3.56; S, 8.12; Cl, 9.00; F, 9.65. Found: C, 57.80; H, 3.66; N, 3.72; S,8.29; Cl, 9.05; F, 9.71%.

Example 172-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]-3-methoxypyridine

In a similar manner to Example 13, the title compound (71 mg, 87%) ascolorless columnar crystals by the synthesis using the2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-3-methoxypyridineobtained in Example 9 and recrystallization from ethanol.

¹H-NMR(400 MHz,CDCl₃)δ: 3.72(3H,s), 6.62(1H,s), 6.90-7.04(2H,m),7.09(1H,m), 7.24(1H,m), 7.35(2H,d,J=8.8 Hz), 7.53(2H,d,J=8.8 Hz),8.18(1H,m), 8.30(1H,m).

mp: 184 to 185° C.

Elemental Analysis for C₁₉H₁₄ClF₂NO₃S: Calculated: C, 55.68; H, 3.44; N,3.42; S, 7.82; Cl, 8.65; F, 9.27. Found: C, 55.68; H, 3.45; N, 3.60; S,7.98; Cl, 8.74; F, 9.23.

Example 183-Allyloxy-2-[[(4-chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]pyridine

In a similar manner to Example 13, the title compound (135 mg, 80%) ascolorless needle crystals by the synthesis using the3-allyloxy-2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]pyridineobtained in Example 10 and crystallization from ethanol.

¹H-NMR(400 MHz,CDCl₃)δ: 4.38(1H,m), 4.46(1H,m), 5.29(1H,dd,J=1.2,10.4Hz), 5.35(1H,dd,J=1.2,17.2 Hz), 5.93(1H,m), 6.68(1H,s), 6.91-7.04(2H,m),7.08(1H,m), 7.22(1H,dd,J=4.8,8.4 Hz), 7.34(2H,d,J=8.8 Hz),7.53(2H,d,J=8.8 Hz), 8.17(1H,m), 8.31(1H,m).

mp: 119 to 120° C.

Elemental Analysis for C₂₁H₁₆ClF₂NO₃S: Calculated: C, 57.87; H, 3.70; N,3.21; S, 7.36; Cl, 8.13; F, 8.72. Found: C, 57.90; H, 3.75; N, 3.37; S,7.51; Cl, 8.20; F, 8.73.

Example 193-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]pyridine

In a similar manner to Example 13, the title compound (118 mg, 86%) ascolorless needle crystals by the synthesis using the3-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]pyridine obtainedin Example 11 and purification by silica gel chromatography(hexane:ethyl acetate=4:1).

¹H-NMR(400 MHz,CDCl₃)δ: 5.68(1H,s), 6.91-7.07(2H,m), 7.34(1H,m),7.40(2H,d,J=8.4 Hz), 7.57(2H,d,J=8.4 Hz), 7.76(1H,m), 8.04(1H,m),8.53(1H,d,J=2.0 Hz), 8.59(1H,m).

mp: 130 to 131° C.

Elemental Analysis for C₁₈H₁₂ClF₂NO₂S: Calculated: C, 56.92; H, 3.18; N,3.69; S, 8.44; Cl, 9.33; F, 10.00. Found: C, 56.87; H, 3.16; N, 3.74; S,8.51; Cl, 9.34; F, 10.00.

Example 204-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]pyridine

The 2,5-difluorophenyl-4-pyridylmethanol (75 mg, 0.34 mmol) obtained inReferential Example 18 was dissolved in thionyl chloride (1.0 ml). Acatalytic amount of dimethylformamide was added to the resultingsolution and the mixture was stirred for 14 hours. The reaction mixturewas concentrated under reduced pressure. To the residue was addeddioxane. The resulting mixture was concentrated further. The residuethus obtained was dissolved in dimethylformamide (5 ml), followed by theaddition of 4-chlorobenzenethiol (74 mg, 0.51 mmol) and potassiumcarbonate (281 mg, 2.04 mmol) under a nitrogen atmosphere. The resultingmixture was stirred at 50° C. for 1 hour. After the reaction mixture wascooled to room temperature, diethyl ether (50 ml) was added thereto. Theresulting mixture was washed with water and brine. The organic layer wasdried over magnesium sulfate, and concentrated under reduced pressure.The residue was subjected to silica gel chromatography (hexane:ethylacetate=1:1) to give a mixture containing4-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]pyridine.

To a methanol (12 ml) solution of the mixture were added hexaammoniumheptamolybdate tetrahydrate (60 mg) and 30% aqueous hydrogen peroxide (6ml) sequentially. The resulting mixture was stirred for 65 hours. To thereaction mixture was added ethyl acetate (80 ml). The resulting mixturewas washed with water and brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure to remove the solvent. Theresidue was purified by silica gel chromatography (hexane:ethylacetate=4:1 to 1:1) to give the title compound (51 mg, 39%).Recrystallization of the compound from ethanol yielded colorless needlecrystals.

¹H-NMR(400 MHz,CDCl₃)δ: 5.64(1H,s), 6.91-7.06(2H,m), 7.40(2H,d,J=8.0Hz), 7.45(2H,d,J=4.8 Hz), 7.58(2H,d,J=8.0 Hz), 7.70(1H,s),8.61(2H,d,J=4.8 Hz).

mp: 126 to 127° C.

Elemental Analysis for C₁₈H₁₂ClF₂NO₂S: Calculated: C, 56.92; H, 3.18; N,3.69; S, 8.44; Cl, 9.33; F, 10.00. Found: C, 56.66; H, 3.16; N, 3.83; S,8.58; Cl, 9.32; F, 9.99.

Example 215-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]pyrimidine

In a similar manner to Example 13, the title compound (71 mg, 87%:yield: two steps after the5-[(2,5-difluorophenyl)-hydroxymethyl]pyrimidine obtained in ReferentialExample 12) as colorless columnar crystals by the synthesis using the5-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]pyrimidine obtainedin Example 12 and purification by silica gel chromatography(hexane:ethyl acetate=5:1).

¹H-NMR(400 MHz,CDCl₃)δ: 5.65(1H,s), 6.93-7.10(2H,m), 7.43(2H,d,J=8.8Hz), 7.61(2H,d,J=8.8 Hz), 7.73(1H,m), 8.90(2H,s), 9.21(1H,s). mp: 136 to137° C.

Elemental Analysis for C₁₇H₁₁ClF₂N₂O₂S: Calculated: C, 53.62; H, 2.91;N, 7.36; S, 8.42; Cl, 9.31; F, 9.98. Found: C, 53.64; H, 2.83; N, 7.44;S, 8.61; Cl, 9.34; F, 9.96.

Example 223-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-4-hydroxychromen-2-one

After glacial acetic acid (60 mg, 1 mmol) and pyridine (80.5 μl, 1 mmol)were added to an ethanol (4 ml) solution of 2,5-difluorobenzaldehyde(109 μl, 1 mmol), 4-hydroxycoumarine (162 mg, 1 mmol) and4-chlorothiophenol (144.6 mg, 1 mmol) at room temperature, the resultingmixture was stirred for 24 hours. The precipitate thus formed wascollected by filtration and washed with a small amount of ethanol togive the title compound (345 mg, 80%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 6.16(1H,s), 6.95-7.12(3H,m), 7.24-7.27(1H,m),7.27(2H,d,J=8.8 Hz), 7.32(1H,t,J=7.6 Hz), 7.43(2H,d,J=8.8 Hz),7.56(1H,m), 7.94(1H,dd,J=1.6,7.6 Hz).

mp: 146 to 147° C.

MSm/z: 431(M⁺+H).

Example 233-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]-4-methoxychromen-2-one(Compound A) and3-[[(4-chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]-2-methoxychromen-4-one(Compound B)

A hexane solution of (0.41 ml, 0.822 mmol) of 2Ntrimethylsilyldiazomethane was added in portions to a benzene-methanol(10:1) solution of3-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-4-hydroxychromen-2-one(118 mg, 0.274 mmol) at room temperature. The resulting mixture wasstirred for 5 minutes. After acetic acid was added until the solutionbecame colorless, the reaction mixture was concentrated under reducedpressure.

The residue was dissolved in methanol (12 ml). To the resulting solutionwere added 30% aqueous hydrogen peroxide (6 ml) and hexaammoniumheptamolybdate tetrahydrate (60 mg). The resulting mixture was stirredfor 20 hours. Ethyl acetate (50 ml) was added to the reaction mixture.The resulting mixture was washed with water and brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (hexane:ethylacetate=5:1 to 3:1) to give a nonpolar compound (22 mg, 17%) as needlecrystals, and a polar compound (9.0 mg, 7%) as a white solid aftersolidification from hexane. As a result of the NOE (nuclear Overhausereffect) test of the nonpolar compound, NOE was observed between themethoxy and hydrogen at the 5-position of the chromenone. In the test ofthe polar compound, on the other hand, NOE was not observed between themethoxy and the hydrogen on the aromatic ring of chromenone but wasobserved between the methoxy and the hydrogen at the 6-position on thedifluorobenzene ring. Based on this result, the structure of thenonpolar compound was identified as3-[[(4-chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]-4-methoxychromen-2-one(Compound A) and that of the polar compound was identified as3-[[(4-chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]-2-methoxychromen-4-one(Compound B).

Compound A

¹H-NMR(400 MHz,CDCl₃)δ: 4.13(3H,s), 6.39(1H,s), 6.88(1H,m), 6.98(1H,m),7.3-7.4(2H,m), 7.43(2H,d,J=8.8 Hz), 7.58(1H,m), 7.70(2H,d,J=8.8 Hz),7.73(1H,m), 8.09(1H,m).

mp: 178 to 179° C.

Elemental Analysis for C₂₃H₁₅ClF₂O₃S: Calculated: C, 57.93; H, 3.17; S,6.72; Cl, 7.43; F, 7.97. Found: C, 57.59; H, 3.14; S, 6.85; Cl, 7.52; F,8.01.

Compound B

¹H-NMR(400 MHz,CDCl₃)δ: 4.23(3H,s), 6.54(1H,s), 6.89(1H,m); 6.96(1H,m),7.41(2H,d,J=8.4 Hz), 7.4-7.46(2H,m), 7.63(1H,m), 7.73(2H,d,J=8.4 Hz),8.02(1H,m), 8.14(1H,dd,J=1.6,8.0 Hz).

mp: 162 to 163° C.

FAB-MS: 477.0366 (Calcd for C₂₃H₁₆ClF₂O₅S: 477.0375).

Example 242-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-1-methyl-1H-benzimidazole

Trifluoroacetic acid (2.0 ml) was added to the2-[(t-butoxycarbonyloxy)-(2,5-difluorophenyl)methyl]-1-methyl-1H-benzimidazole(204 mg, 0.545 mmol) obtained in Referential Example 13. The resultingmixture was stirred at room temperature for 30 minutes. The reactionmixture was concentrated under reduced pressure. Dioxane was added tothe residue, followed by further concentration under reduced pressure.The residue was dissolved in thionyl chloride (1.0 ml). One drop ofdimethylformamide was added to the resulting solution. The resultingmixture was stirred for 16 hours at room temperature. The reactionmixture was concentrated under reduced pressure. Dioxane was added tothe residue and the resulting mixture was concentrated further underreduced pressure. The residue was dissolved in dimethylformamide (5.0ml). After addition of 4-chlorobenzenethiol (118 mg, 0.82 mmol) andpotassium carbonate (451 mg, 3.27 mmol), the resulting mixture wasstirred at 50° C. for 2 hours. The reaction mixture was then allowed tostand at room temperature and ethyl acetate (60 ml) was added thereto.The resulting mixture was washed with water and brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue thus obtained was purified by silica gel chromatography(hexane:ethyl acetate=10:1 to 5:1) to give the title compound (195 mg,89%) as a colorless oil.

¹H-NMR(400 MHz,CDCl₃)δ: 3.67(3H,s), 5.91(1H,s), 6.87-6.93(2H,m),7.19(2H,d,J=8.8 Hz), 7.27(2H,d,J=8.8 Hz), 7.25-7.33(3H,m), 7.60(1H,m),7.85(1H,m).

MSm/z: 401 (M⁺+H).

Example 252-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-1-methyl-5-chloro-1H-imidazole

Trifluoroacetic acid (10 ml) was added to the2-[(t-butoxycarbonyloxy)-(2,5-difluorophenyl)methyl]-1-methyl-5-chloro-1H-imidazole(404 mg, 1.13 mmol) obtained in Referential Example 14. The resultingmixture was stirred at room temperature for 3 hours. The reactionmixture was concentrated under reduced pressure. Dioxane was added tothe residue, followed by further concentration under reduced pressure.The residue was dissolved in thionyl chloride (2.0 ml) and to theresulting solution was added a drop of dimethylformamide. The mixturewas stirred at room temperature for 17 hours. The reaction mixture wasconcentrated under reduced pressure. Dioxane was added to the residue,followed by further concentration under reduced pressure. The residuewas dissolved in dimethylformamide (5.0 ml). To the resulting solutionwere added 4-chlorobenzenethiol (244 mg, 1.69 mmol) and potassiumcarbonate (936 mg, 6.78 mmol). The resulting mixture was stirred at 50°C. for 2 hours. The reaction mixture was allowed to stand until itbecame room temperature. Ethyl ether (60 ml) was added. The resultingmixture was washed with water and brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (hexane:ethyl acetate=10:1 to 5:1)to give the title compound (195 mg, 89%) as a colorless oil.

¹H-NMR(400 MHz,CDCl₃)δ: 3.57(3H,s), 5.67(1H,s), 6.89-6.95(2H,m),6.97(1H,s), 7.20(2H,d,J=8.4 Hz), 7.21(2H,d,J=8.4 Hz), 7.54(1H,m). MSm/z:386(M⁺+H).

Example 26 2-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]thiazole

The 2-[(2,5-difluorophenyl)-hydroxymethyl]thiazole (348 mg, 1.53 mmol)obtained in Referential Example 15 was dissolved in thionyl chloride(1.5 ml). To the resulting solution was added a drop ofdimethylformamide. The resulting mixture was stirred at room temperaturefor 14 hours. The reaction mixture was concentrated under reducedpressure. Dioxane was added to the residue, followed by furtherconcentration under reduced pressure. The residue was dissolved indimethylformamide (10.0 ml). To the resulting solution were added4-chlorobenzenethiol (332 mg, 2.3 mmol) and potassium carbonate (845 mg,6.12 mmol). The resulting mixture was stirred at 50° C. for 2 hours.After the reaction mixture was allowed to stand until it became roomtemperature, ethyl acetate (60 ml) was added thereto. The resultingmixture was washed with water and brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (hexane:ethyl acetate=10:1 to 6:1)to give the title compound (130 mg, 24%) as a colorless oil.

¹H-NMR(400 MHz,CDCl₃)δ: 6.04(1H,s), 6.90-7.06(2H,m), 7.22(2H,d,J=8.4Hz), 7.30(2H,d,J=8.4 Hz), 7.15-7.35(2H,m), 7.76 (1H,d, J=3.2 Hz).

MSm/z: 354(M⁺+H).

Example 272-[[(4-Chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-1-(4-methoxyphenyl)-1H-imidazole

Trifluoroacetic acid (10 ml) was added to the2-[(t-butoxycarbonyloxy)-(2,5-difluorophenyl)methyl]-1-(4-methoxyphenyl)-1H-imidazole(667 mg, 1.6 mmol) obtained in Referential Example 16. The resultingmixture was stirred at room temperature for 3 hours. The reactionmixture was concentrated under reduced pressure. Dioxane was added tothe residue, followed by further concentration under reduced pressure.The residue was dissolved in thionyl chloride (2.0 ml) and to theresulting solution was added a drop of dimethylformamide. The resultingmixture was stirred at room temperature for 17 hours. The reactionmixture was concentrated under reduced pressure. To the residue wasadded dioxane, followed by further concentration under reduced pressure.The residue was dissolved in dimethylformamide (5.0 ml). To theresulting solution were added 4-chlorobenzenethiol (347 mg, 2.4 mmol)and potassium carbonate (1.32 g, 9.6 mmol). The resulting mixture wasstirred at 50° C. for 2 hours. After the reaction mixture was allowed tostand until it became room temperature, ethyl ether (60 ml) was addedthereto. The resulting mixture was washed with water and brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel chromatography(hexane:ethyl acetate=10:1 to 5:1), followed by crystallization fromethanol to give the title compound (535 mg, 75%) as colorless needlecrystals.

¹H-NMR(400 MHz,CDCl₃)δ: 3.86(3H,s), 5.57(1H,s), 6.8-6.9(3H,m),6.91(2H,d,J=8.4 Hz), 7.00(2H,d,J=8.4 Hz), 7.06(2H,d,J=6.8 Hz),7.11(2H,d,J=6.8 Hz), 7.16(1H,s), 7.81(1H,m).

MSm/z: 443(M⁺+H).

Example 282-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]-1-methyl-1H-benzimidazole(Compound A) and2-[[(4-chlorophenyl)sulfinyl]-(2,5-difluorophenyl)methyl]-1-methyl-1H-benzimidazole(Compound B)

Hexaammonium heptamolybdate tetrahydrate (60 mg) was added to a methanol(12 ml) solution of the2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-1-methyl-1H-benzimidazole(190 mg, 0.474 mmol) obtained in Example 24. To the resulting mixturewas added 30% aqueous hydrogen peroxide (6 ml), followed by stirring for17 hours. Ethyl acetate (60 ml) was added to the reaction mixture. Theresulting mixture was washed with water and brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (hexane:ethyl acetate=6:1 to4:1) to give a nonpolar compound (Compound A) (48 mg, 23%) and a polarcompound (Compound B) (23 mg, 12%) were obtained as needle crystals anda white solid, respectively.

Compound A

¹H-NMR(400 MHz,CDCl₃)δ: 3.90(3H,s), 6.14(1H,s), 6.9-7.1(2H,m),7.26-7.42(3H,m), 7.39(2H,d,J=8.8 Hz), 7.46(2H,d,J=8.8 Hz),7.81(1H,d,J=8.0 Hz), 8.16(1H,m).

mp: 213 to 214° C.

Elemental Analysis for C₂₁H₁₅ClF₂N₂OS: Calculated: C, 58.27; H, 3.49; N,6.47; S, 7.41; Cl, 8.19; F, 8.78. Found: C, 58.08; H, 3.62; N, 6.53; S,7.35; Cl, 8.10; F, 8.74.

Compound B

¹H-NMR(400 MHz,CDCl₃)δ: 3.35( 3/2H,s), 3.78( 3/2H,s), 5.52(½H,s),5.57(½H,s), 6.78-7.1(2H,m), 7.2-7.4(7H,m), 7.76-7.95(2H,m).

mp: 130-131° C.

FAB-MS: 477.0646 (Calcd for C₂₁H₁₆ClF₂N₂OS: 477.0640).

Example 292-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]-1-methyl-5-chloro-1H-imidazole

Hexaammonium heptamolybdate tetrahydrate (60 mg) was added to a methanol(12 ml) solution of the2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-1-methyl-5-chloro-1H-imidazole(141 mg, 0.37 mmol) obtained in Example 25. To the resulting mixture wasadded 30% aqueous hydrogen peroxide (6 ml), followed by stirring for 64hours. Ethyl acetate (60 ml) was added to the reaction mixture. Theresulting mixture was washed with water and brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas crystallized from ethanol to give the title compound (103 mg, 67%)as colorless needle crystals.

¹H-NMR(400 MHz,CDCl₃)δ: 3.71(3H,s), 5.88(1H,s), 6.93-7.08(2H,m),7.03(1H,s), 7.43(4H,s), 7.98(1H,m).

mp: 179 to 180° C.

Elemental Analysis for C₁₇H₁₂Cl₂F₂N₂O₂S: Calculated: C, 48.90; H, 2.93;N, 6.71; S, 7.68; Cl, 16.99; F, 9.11. Found: C, 48.90; H, 2.93; N, 6.77;S, 7.80; Cl, 17.02;F, 9.19.

Example 302-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]thiazole

Hexaammonium heptamolybdate tetrahydrate (30 mg) was added to a methanol(6.0 ml) solution of the2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]thiazole (124 mg,0.35 mmol) obtained in Example 26. To the resulting mixture was added30% aqueous hydrogen peroxide (3 ml) and the mixture was stirred for 15hours. Ethyl acetate (60 ml) was added to the reaction mixture. Theresulting mixture was washed with water and brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas crystallized from ethanol to give the title compound (91 mg, 67%) ascolorless columnar crystals.

¹H-NMR(400 MHz,CDCl₃)δ: 6.21(1H,s), 6.92-7.08(2H,m), 7.41(2H,d,J=8.8Hz), 7.45(1H,d,J=3.6 Hz), 7.56(2H,d,J=8.8 Hz), 7.86(1H,d,J=3.6 Hz),7.94(1H,m).

mp: 163 to 164° C.

Elemental Analysis for C₁₆H₁₀ClF₂NO₂S₂: Calculated: C, 49.81; H, 2.61;N, 3.63; S, 16.62; Cl, 9.19; F, 9.85. Found: C, 49.98; H, 2.61; N, 3.77;S, 16.60; Cl, 9.25; F, 9.87.

Example 312-[[(4-Chlorophenyl)sulfonyl]-(2,5-difluorophenyl)methyl]-1-(4-methoxyphenyl)-1H-imidazole

Hexaammonium heptamolybdate tetrahydrate (60 mg) was added to a methanol(12 ml) solution of the2-[[(4-chlorophenyl)thio]-(2,5-difluorophenyl)methyl]-1-(4-methoxyphenyl)-1H-benzimidazole(118 mg, 0.27 mmol) obtained in Example 27. To the resulting mixture wasadded 30% aqueous hydrogen peroxide (6 ml), followed by stirring for 64hours. Ethyl acetate (60 ml) was added to the reaction mixture. Theresulting mixture was washed with water and brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas crystallized from ethanol to give the title compound (76 mg, 60%) ascolorless needle crystals.

¹H-NMR(400 MHz,CDCl₃)δ: 3.89(3H,s), 5.83(1H,s), 6.93-7.05(4H,m),6.97(2H,d,J=8.8 Hz), 7.01(2H,d,J=8.8 Hz), 7.38(2H,d,J=8.8 Hz),7.41(2H,d,J=8.8 Hz), 8.15(1H,m).

mp: 150 to 151° C.

Elemental Analysis for C₂₃H₁₇ClF₂N₂O₃S: Calculated: C, 58.13; H, 3.61;N, 5.90; S, 6.75; Cl, 7.47; F, 8.00. Found: C, 58.09; H, 3.51; N, 5.99;S, 6.88; Cl, 7.48; F, 8.06.

Example 32 5-Chloro-2-[(2,5-difluorophenyl-4-pyridylmethyl)thio]pyridine

Triethylamine (0.279 ml, 2.00 mmol) and then, methanesulfonyl chloride(0.116 ml, 1.50 mmol) were added to a dichloromethane (10 ml) solutionof the 2,5-difluorophenyl-4-pyridylmethanol (221 mg, 1.00 mmol) obtainedin Referential Example 18 at 0° C. The resulting mixture was stirred for3 hours at room temperature. The reaction mixture was washed with asaturated aqueous solution of sodium bicarbonate. The organic layer wasdried over anhydrous sodium sulfate and then, filtered. The filtrate wasconcentrated under reduced pressure. To an N,N-dimethylformamide (10 ml)solution of the residue thus obtained were added the5-chloro-2-pyridinethiol (145 mg, 1.00 mmol) obtained in ReferentialExample 17 and potassium carbonate (166 mg, 1.20 mmol) sequentially. Theresulting mixture was stirred at room temperature for 2 hours. Ethylacetate was added to the reaction mixture. The resulting mixture waswashed with water. The organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated under reducedpressure. The residue was subjected to flash silica gel chromatography,and the fraction obtained from the hexane:ethyl acetate=17:3 eluate wasconcentrated under reduced pressure to give the title compound (267 mg,0.77 mmol, 77%) as a yellow solid.

¹H-NMR(400 MHz,CDCl₃)δ: 6.52(1H,s), 6.92-6.98(1H,m), 6.99-7.06(1H,m),7.48(1H,dd,J=8.5,0.7 Hz), 7.17-7.23(1H,m), 7.34(2H,d,J=6.1 Hz),7.47(1H,dd,J=8.5,2.4 Hz), 8.33(1H,dd,J=2.4,0.7 Hz), 8.54(2H,d,J=6.1 Hz).

MSm/z: 349(M⁺+H).

Example 335-Chloro-2-[(2,5-difluorophenyl-4-pyridylmethyl)sulfonyl]pyridine

To a methanol (6 ml) solution of5-chloro-2-[(2,5-difluorophenyl-4-pyridylmethyl)thio]pyridine (239 mg,0.68 mmol) was added a water (12 ml) solution of oxone (potassiumperoxomonosulfate compound, 2KHSO₅.KHSO₄.K₂SO₄) (631 mg, 1.03 mmol) at0° C. After the reaction mixture was stirred at room temperature for 3days, dichloromethane was added thereto. The resulting mixture waswashed with a saturated aqueous solution of sodium bicarbonate. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure. The residue waspurified by preparative high performance liquid chromatography (using amixed solvent system of water/acetonitrile/formic acid). The solid thusobtained was washed with hexane/diisopropyl ether and then collected byfiltration to give the title compound (67 mg, 0.18 mmol, 26%) as a whitepowder.

¹H-NMR(400 MHz,CDCl₃)δ: 6.44(1H,s), 6.96-7.08(2H,m), 7.48(2H,d,J=6.3Hz), 7.70-7.77(1H,m), 7.79(1H,dd,J=8.3,2.2 Hz), 7.84(1H,dd,J=8.3,0.7Hz), 8.61(2H,d,J=6.3 Hz), 8.67(1H,dd,J=2.2,0.7 Hz).

Elemental Analysis for C₁₇H₁₁ClF₂N₂O₂S: Calculated: C, 53.62; H, 2.91;F, 9.98; N, 7.36; S, 8.42. Found: C, 53.55; H, 2.87; F, 10.10; N, 7.40;S, 8.55.

MSm/z: 381(M⁺+H).

Example 344-[[(4-Chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]tetrahydropyrane

The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (200 mg,0.661 mmol) obtained in Referential Example 1 andtetrahydro-4H-pyran-4-ol (0.13 ml, 1.36 mmol) were dissolved in toluene(10 ml). After addition of cyanomethylenetri-n-butylphosphorane (330 mg,1.37 mmol), the resulting mixture was heated under reflux for 14 hoursin an argon atmosphere. The reaction mixture was then allowed to cool.After the addition of cyanomethylenetri-n-butylphosphorane (200 mg,0.829 mmol), the resulting mixture was heated under reflux for 14 hoursunder an argon atmosphere. The reaction mixture was allowed to cool, andthen concentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel chromatography, and the fraction obtainedfrom the hexane:ethyl acetate=4:1 eluate was concentrated under reducedpressure to afford a white solid. The resulting white solid was washedwith hexane to give the title compound (157 mg, 0.406 mmol, 61%) as awhite powder.

¹H-NMR(400 MHz,CDCl₃)δ: 1.28-1.48(2H,m), 1.71(1H,ddd,J=25.3,11.7,4.3Hz), 2.37(1H,brd,J=12.7 Hz), 2.70-2.88(1H,m), 3.40(1H,td,J=11.7,2.5 Hz),3.50(1H,td,J=12.0,2.2 Hz), 3.91(1H,dm,J=11.2 Hz), 4.02(1H,dm,J=11.7 Hz),4.46(1H,d,J=8.8 Hz), 6.68-6.80(1H,m), 6.88-6.98(1H,m), 7.31(2H,d,J=8.5Hz), 7.36-7.45(1H,m), 7.49(2H,d,J=8.5 Hz).

mp: 150 to 152° C.

MSm/z: 387(M⁺+H).

Elemental Analysis for C₁₈H₁₇ClF₂O₃S: Calculated: C, 55.89; H, 4.43; Cl,9.16; F, 9.82; S, 8.29. Found: C, 55.64; H, 4.27; Cl, 9.41; F, 9.89; S,8.28.

Example 354-[[(4-Chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]tetrahydrothiopyrane

The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (500 mg, 1.65mmol) obtained in Referential Example 1 and the tetrahydrothiopyran-4-ol(400 mg, 3.38 mmol) obtained in Referential Example 19 were dissolved intoluene (20 ml). After addition of cyanomethylenetri-n-butylphosphorane(800 mg, 3.31 mmol), the resulting mixture was heated under reflux for14 hours under an argon atmosphere. The reaction mixture was allowed tocool, and cyanomethylenetri-n-butylphosphorane (400 mg, 1.66 mmol) wasadded thereto. Under an argon atmosphere, the resulting mixture washeated under reflux for 14 hours. The reaction mixture was allowed tocool, and then concentrated under reduced pressure. The residue thusobtained was subjected to flash silica gel chromatography. The fractionobtained from the hexane:ethyl acetate=15:1 eluate was concentratedunder reduced pressure to afford a white solid. The resulting whitesolid was washed with a hexane/diisopropyl ether mixture to give thetitle compound (404 mg, 1.00 mmol, 61%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 1.47(1H,ddd,J=23.4,10.0,3.3 Hz),1.68(1H,ddd,J=25.0,11.4,3.3 Hz), 2.13(1H,dm,J=11.4 Hz), 2.50-2.78(5H,m),2.82(1H,td,J=12.8,2.6 Hz), 4.47(1H,d,J=7.3 Hz), 6.72-6.82(1H,m),6.90-7.00(1H,m), 7.31(2H,d,J=8.8 Hz), 7.40-7.60(1H,m), 7.49(2H,d,J=8.8Hz).

mp: 150 to 152° C.

MSm/z: 403(M⁺+H).

Elemental Analysis for C₁₈H₁₇ClF₂O₂S₂: Calculated: C, 53.66; H, 4.25;Cl, 8.80; F, 9.43; S, 15.92. Found: C, 53.52; H, 4.21; Cl, 9.00; F,9.54; S, 15.88.

Example 364-[[(4-Chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]tetrahydrothiopyrane-1,1-dioxide(Compound A) and4-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]tetrahydrothiopyran-1-oxide(Compound B (Isomer A) and Compound B (Isomer B))

After4-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]tetrahydrothiopyrane(360 mg, 0.893 mmol) was dissolved in dichloromethane (15 ml),3-chloroperbenzoic acid (320 mg, 1.85 mmol) was added to the resultingsolution under ice cooling. After stirring at room temperature for 14hours, the reaction mixture was concentrated under reduced pressure. Theresidue thus obtained was subjected to flash silica gel chromatography,and the fraction obtained from the hexane:ethyl acetate=1:1 eluate wasconcentrated under reduced pressure to afford a white solid. Theresulting white solid was dissolved in dichloromethane. The resultingsolution was washed sequentially with a 1N aqueous sodium hydroxidesolution and brine. The organic layer was dried over anhydrous magnesiumsulfate. After filtration, the filtrate was concentrated under reducedpressure to afford a white solid. The resulting white solid was washedwith diethyl ether to give the title Compound A (187 mg, 0.430 mmol,48%) as a white powder. Moreover, the fraction obtained from thedichloromethane:methanol=50:1 eluate was concentrated under reducedpressure to give a mixture of the title Compound B (Isomer A) and thetitle Compound B (Isomer B) as a white solid. The resulting mixture wasseparated and purified by flash silica gel chromatography(dichloromethane:methanol=80:1). The white solids thus obtained werewashed with diethyl ether to give the title Compound B (Isomer A) (lowpolarity) (78 mg, 0.19 mmol, 21%) as a white powder and the titleCompound B (Isomer B) (high polarity) (69 mg, 0.17 mmol, 19%) as a whitepowder.

Compound A

¹H-NMR(400 MHz,CDCl₃)δ: 1.85-2.00(1H,m), 2.18-2.35(2H,m),2.68-2.91(2H,m), 2.98-3.10(2H,m), 3.10-3.28(2H,m), 4.54(1H,brd,J=7.1Hz), 6.74-6.90(1H,m), 6.94-7.06(1H,m), 7.33(2H,d,J=8.7 Hz),7.35-7.55(1H,m), 7.49(2H,d,J=8.7 Hz).

mp: 245 to 248° C.

Elemental Analysis for C₁₈H₁₇ClF₂O₄S₂: Calculated: C, 49.71; H, 3.94;Cl, 8.15; F, 8.74; S, 14.75. Found: C, 49.38; H, 3.87; Cl, 8.50; F,8.86; S, 14.62.

Compound B (Isomer A)

¹H-NMR(400 MHz,CDCl₃)δ: 1.76(1H,brd,J=13.4 Hz), 2.18(1H,ddm,J=25.4,12.5Hz), 2.32-2.70(4H,m), 2.74-2.90(1H,m), 2.98(1H,dm,J=14.0 Hz),3.09(1H,dm,J=14.4 Hz), 4.53(1H,d,J=7.3 Hz), 6.72-6.86(1H,m),6.90-7.02(1H,m), 7.32(2H,d,J=8.5 Hz), 7.40-7.60(1H,m), 7.49(2H,d,J=8.5Hz).

mp: 255 to 256° C.

Elemental Analysis for C₁₈H₁₇ClF₂O₃S₂: Calculated: C, 51.61; H, 4.09;Cl, 8.46; F, 9.07; S, 15.31. Found: C, 51.51; H, 4.04; Cl, 8.69; F,9.15; S, 15.20.

Compound B (Isomer B)

¹H-NMR(400 MHz,CDCl₃)δ: 1.42(1H,ddm,J=22.3,11.7 Hz),1.92(1H,ddm,J=11.7,11.0 Hz), 2.14-2.27(1H,m), 2.66(1H,td,J=12.2,2.7 Hz),2.70-2.90(3H,m), 3.10-3.24(1H,m), 3.32-3.44(1H,m), 4.49(1H,d,J=8.1 Hz),6.72-6.85(1H,m), 6.90-7.02(1H,m), 7.32(2H,d,J=8.5 Hz), 7.34-7.50(1H,m),7.48(2H,d,J=8.5 Hz)

mp: 184 to 187° C.

Elemental Analysis for C₁₈H₁₇ClF₂O₃S₂: Calculated: C, 51.61; H, 4.09;Cl, 8.46; F, 9.07; S, 15.31. Found: C, 51.82; H, 4.23; Cl, 8.42; F,9.12; S, 15.07.

Example 37 t-Butyl4-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]-1-piperidinecarboxylate

The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (1.25 g, 4.13mmol) obtained in Referential Example 1 and t-butyl4-hydroxy-1-piperidinecarboxylate (1.70 g, 8.44 mmol) were dissolved intoluene (50 ml). To the resulting solution was addedcyanomethylenetri-n-butylphosphorane (2.00 g, 8.29 mmol). The resultingmixture was heated under reflux for 14 hours under an argon atmosphere.The reaction mixture was allowed to cool and then, concentrated underreduced pressure. The residue thus obtained was subjected to flashsilica gel chromatography. The fraction obtained from the hexane:ethylacetate=1:1 eluate was concentrated under reduced pressure to give awhite solid. The resulting white solid was washed with diethyl ether togive the title compound (1.68 g, 3.46 mmol, 84%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 1.10-1.25(1H,m), 1.40-1.70(2H,m), 1.44(9H,s),2.30-2.50(1H,m), 2.60-2.95(3H,m), 4.00-4.25(2H,m), 4.45(1H,d,J=7.8 Hz),6.69-6.80(1H,m), 6.88-6.98(1H,m), 7.31(2H,d,J=8.6 Hz), 7.35-7.50(1H,m),7.49(2H,d,J=8.6 Hz).

mp: 193 to 196° C.

Elemental Analysis for C₂₃H₂₆ClF₂NO₄S: Calculated: C, 56.84; H, 5.39;Cl, 7.30; F, 7.82; N, 2.88; S, 6.60. Found: C, 56.41; H, 5.43; Cl, 7.77;F, 7.61; N, 2.99; S, 6.58.

Example 384-[[(4-Chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]piperidinehydrochloride

In dichloromethane (50 ml) was dissolved t-butyl4-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]-1-piperidinecarboxylate(1.56 g, 3.21 mmol). Trifluoroacetic acid (5.0 ml) was added dropwise tothe resulting solution under ice cooling. The reaction mixture wasstirred at room temperature for 2 hours and then, concentrated underreduced pressure. To the residue thus obtained were addeddichloromethane (10 ml) and a 1N hydrochloric acid-ethanol solution (10ml). The resulting mixture was concentrated under reduced pressure togive a white solid. The resulting solid was washed with diethyl ether togive the title compound (1.36 g, 3.12 mmol, 97%) as a white powder.

¹H-NMR(400 MHz,CD₃OD)δ: 1.38-1.52(1H,m), 1.70-1.92(2H,m),2.73(1H,brd,J=14.2 Hz), 2.86-3.00(1H,m), 3.05(1H,td,J=12.9,3.1 Hz),3.13(1H,td,J=13.1,3.1 Hz), 3.30-3.40(1H,m), 3.48(1H,dm,J=13.0 Hz),4.72(1H,d,J=8.6 Hz), 6.82-6.98(1H,m), 7.04-7.12(1H,m), 7.40-7.55(1H,m),7.44(2H,d,J=8.6 Hz), 7.57(2H,d,J=8.6 Hz).

mp: 184 to 190° C.

Elemental Analysis for C₁₈H₁₈ClF₂NO₂S.HCl.0.75H₂O: Calculated: C, 49.61;H, 4.74; Cl, 16.27; F, 8.72; N, 3.21; S, 7.36. Found: C, 49.57; H, 4.75;Cl, 15.79; F, 9.16; N, 3.34; S, 7.25.

Example 392-[(4-Chlorophenylthio)-(2,5-difluorophenyl)methyl]-5-[(4-chlorophenylthio)methyl]pyridine

An ethanol (15 ml) suspension of sodium borohydride (33 mg, 0.88 mmol)was cooled to −78° C. While stirring, an ethanol solution (10 ml) of the[6-(2,5-difluorophenylcarbonyl)pyridin-3-yl]methyl acetate (510 mg, 1.75mmol) obtained in Referential Example 21 was added to the suspension inportions. The reaction mixture was stirred for 30 minutes. An aqueoussolution of ammonium chloride was added and the resulting mixture wasallowed to stand until it became room temperature. The reaction mixturewas extracted with ethyl acetate (100 ml). The extract was washed withwater and brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was dissolved in methylene chloride(30 ml), followed by the addition of triethylamine (270 μl) andmethanesulfonyl chloride (270 μl) under ice cooling. The reactionmixture was stirred at room temperature for 3 days. After the additionof water, the mixture was extracted with ethyl acetate (60 ml). Theextract was washed with water and brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue thusobtained was dissolved in N,N-dimethylformamide (25 ml). To theresulting solution were added 4-chlorobenzenethiol (751 mg, 5.3 mmol)and potassium carbonate (718 mg, 5.2 mmol) under a nitrogen atmosphere.The reaction mixture was stirred at 60° C. for 1 hour. After thereaction mixture was cooled to room temperature, diethyl ether (80 ml)was added thereto. The resulting mixture was washed with water andbrine. The organic layer was dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was subjected to silicagel chromatography (hexane:ethyl acetate=10:1) to give the titlecompound (237 mg, 27%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 3.99(2H,s), 5.81(1H,s), 6.90(2H,m),7.15(2H,d,J=8.8 Hz), 7.16(2H,d,J=8.8 Hz), 7.19(4H,d,J=8.8 Hz),7.20(1H,d,J=7.6 Hz), 7.38(1H,m), 7.49(1H,dd,J=2.0,7.6 Hz), 8.38(1H,br).

mp: 87 to 88° C.

Example 402-[(4-Chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]-5-[(4-chlorophenylsulfonyl)methyl]pyridine

Hexaammonium heptamolybdate tetrahydrate (30 mg) was added to a methanol(6.0 ml) solution of2-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]-5-[(4-chlorophenylthio)methyl]pyridine(75 mg, 0.15 mmol), followed by the addition of 30% aqueous hydrogenperoxide (3 ml). The resulting mixture was stirred for 22 hours. Ethylacetate was added to the reaction mixture. The resulting mixture waswashed with water, an aqueous solution of sodium thiosulfate and brine,dried and concentrated under reduced pressure. The residue thus obtainedwas purified by silica gel chromatography (2% MeOH/CHCl₃) to give thetitle compound (70 mg, 62%) as colorless needle crystals.

¹H-NMR(400 MHz,CDCl₃)δ: 4.29(2H,s), 5.91(1H,s), 6.90-7.08(2H,m),7.39(2H,dd,J=1.6,6.8 Hz), 7.45(2H,dd,J=1.6,6.8 Hz), 7.51(2H,d,J=8.8 Hz),7.55(2H,d,J=8.8 Hz), 7.60(1H,d,J=8.0 Hz), 7.65(1H,dd,J=2.4,8.0 Hz),7.91(1H,m), 8.23(1H,s).

mp: 186 to 187° C.

Elemental Analysis for C₂₅H₁₇Cl₂F₂NO₄S₂: Calculated: C, 52.82; H, 3.01;N, 2.46; S, 11.28; Cl, 12.47; F, 6.68. Found: C, 52.88; H, 3.10; N,2.63; S, 11.38; Cl, 12.40; F, 6.83.

Example 412-[(4-Chlorophenylthio)-(2,5-difluorophenyl)methyl]-5-(1,3-dioxolan-2-yl)pyridine

Under a nitrogen atmosphere, triethylamine (1.08 ml, 7.8 mmol) andmethanesulfonyl chloride (0.52 ml, 6.8 mmol) were added to a methylenechloride solution (30 ml) of the2-[(2,5-difluorophenyl)-hydroxymethyl]-5-(1,3-dioxolan-2-yl)pyridine(1.52 g, 5.2 mmol) obtained in Referential Example 22 under ice cooling.The resulting mixture was stirred at room temperature for 3 hours. Afteraddition of a saturated aqueous solution of sodium bicarbonate, theresulting mixture was extracted with ether. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue thus obtained was dissolved indimethylformamide (30 ml). To the resulting solution were addedchlorobenzenethiol (901 mg, 6.2 mmol) and potassium carbonate (1.08 g,7.8 mmol), followed by stirring at 60° C. for 3 hours. After cooling toroom temperature, the reaction mixture was diluted with ether. Thediluted solution was washed with water and brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuethus obtained was purified by silica gel chromatography (hexane:ethylacetate=5:1) to give the title compound (1.56 g, 71%) as colorlessneedle crystals.

¹H-NMR(400 MHz,CDCl₃)δ: 4.0-4.15(4H,m), 5.84(1H,s), 5.92(1H,s),6.85-6.96(2H,m), 7.19(2H,d,J=8.8 Hz), 7.25(2H,d,J=8.8 Hz),7.43(1H,d,J=8.0 Hz), 7.43(1H,m), 7.77(1H,dd,J=2.0,8.0 Hz),8.70(1H,d,J=2.0 Hz).

mp: 70 to 73° C.

MSm/z: 420(M⁺+H).

Example 422-[(4-Chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]-5-(1,3-dioxolan-2-yl)pyridine

Hexaammonium heptamolybdate tetrahydrate (150 mg) was added to amethanol (30 ml) solution of2-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]-5-(1,3-dioxolan-2-yl)pyridine(1.54 g, 3.67 mmol). To the resulting mixture was added 30% aqueoushydrogen peroxide (15 ml), followed by stirring for 24 hours. After thereaction mixture was diluted with ethyl acetate, the diluted solutionwas washed with water and brine and concentrated under reduced pressure.The residue thus obtained was crystallized from ethanol to give thetitle compound (1.22 g, 74%) as colorless needle crystals.

¹H-NMR(400 MHz,CDCl₃)δ: 4.02-4.10(4H,m), 5.85(1H,s), 5.97(1H,s),6.91(1H,m), 6.96(1H,m), 7.38(2H,d,J=8.4 Hz), 7.53(2H,d,J=8.4 Hz),7.63(1H,d,J=7.6 Hz), 7.82(1H,d,J=8.0 Hz), 7.94(1H,m), 8.67(1H,br-s).

mp: 167 to 168° C.

FAB-MS: 452.0544 (Calcd for C₂₁H₁₇ClF₂NO₄S: 452.0535).

Example 432-[(4-Chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]-5-(hydroxymethyl)pyridine

To a 1,4-dioxane solution (30 ml) of2-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]-5-(1,3-dioxolan-2-yl)pyridine(295 mg, 0.54 mmol) was added 1N hydrochloric acid (30 ml). Theresulting mixture was stirred at room temperature for 18 hours. Thereaction mixture was extracted with ethyl acetate. The extract waswashed with water, a saturated aqueous solution of sodium bicarbonate,and brine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure to give a residue.

The residue thus obtained was dissolved in ethanol (10 ml). Under icecooling, sodium borohydride (10 mg, 0.27 mmol) was added to theresulting solution. The resulting mixture was stirred for 1 hour. Waterwas added and the resulting mixture was extracted with ethyl acetate.The extract was washed with water and brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure to give aresidue. The resulting residue was purified by silica gel chromatography(3% methanol/chloroform) to give the title compound (205 mg, 93%) asneedle crystals.

¹H-NMR(400 MHz,CDCl₃)δ: 4.74(2H,s), 5.94(1H,s), 6.91(1H,m), 6.99(1H,m),7.38(2H,d,J=8.4 Hz), 7.53(2H,d,J=8.4 Hz), 7.62(1H,d,J=8.0 Hz),7.76(1H,dd,J=2.0,8.0 Hz), 7.98(1H,m), 8.58 (1H, d, J=2.0 Hz)

mp: 151 to 152° C.

FAB-MS: 410.0444 (Calcd for C₁₉H₁₅ClF₂NO₃S: 410.0429).

Example 44 Methyl3-[6-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]acrylate

To a 1,4-dioxane solution (10 ml) of the2-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]-5-(1,3-dioxolan-2-yl)pyridine(212 mg, 0.47 mmol) obtained in Example 42 was added 1N hydrochloricacid (10 ml). The resulting mixture was stirred at room temperature for19 hours. The reaction mixture was extracted with ethyl acetate. Theextract was washed with water, a saturated aqueous solution of sodiumbicarbonate and brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to afford a residue.

The resulting residue was dissolved in tetrahydrofuran (15 ml). Under anitrogen atmosphere, methyl (triphenylphosphoranylidene)acetate (188 mg,0.56 mmol) was added and the resulting mixture was stirred for 17 hours.The reaction mixture was concentrated under reduced pressure to give aresidue. The resulting residue thus obtained was purified by silica gelchromatography (hexane:ethyl acetate=5:1) to give the title compound(187 mg, 86%) as needle crystals.

¹H-NMR(400 MHz,CDCl₃)δ: 3.80(3H,s), 5.94(1H,s), 6.50(1H,d,J=16.0 Hz),6.91(1H,m), 6.99(1H,m), 7.38(2H,d,J=8.8 Hz), 7.53(2H,d,J=8.8 Hz),7.63(1H,d,J=8.0 Hz), 7.63(1H,d,J=16.0 Hz), 7.84(1H,dd,J=2.0,8.0 Hz),7.98(1H,m), 8.70(1H,d,J=2.0 Hz).

mp: 145 to 146° C.

MSm/z: 464(M⁺+H).

Example 45 Methyl3-[6-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]propionate

Methyl3-[6-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]acrylate(160 mg, 0.34 mmol) was dissolved in ethanol (15 ml). To the resultingsolution was added palladium carbon (30 mg). The resulting mixture wasvigorously stirred under a hydrogen atmosphere of 1 atmospheric pressurefor 24 hours. After the reaction mixture was filtered, the filtrate wasconcentrated under reduced pressure. The residue thus obtained waspurified by silica gel chromatography (hexane:ethyl acetate=5:1) to givethe title compound (94 mg, 58%) as needle crystals.

¹H-NMR(400 MHz,CDCl₃)δ: 2.63(2H,t,J=7.6 Hz), 2.95(2H,t,J=7.6 Hz),3.65(3H,s), 5.89(1H,s), 6.90(1H,m), 6.97(1H,m), 7.36(2H,d,J=8.4 Hz),7.53(2H,d,J=8.4 Hz), 7.55(2H,m), 8.00(1H,m), 8.45(1H,d,J=1.6 Hz).

mp: 121-123° C.

MSm/z: 466(M⁺+H).

Example 463-[6-[(4-Chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]propionicacid

In tetrahydrofuran (5 ml) was dissolved methyl3-[6-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]propionate(92 mg, 0.20 mmol). An aqueous solution (3 ml) of lithium hydroxide (23mg, 0.5 mmol) was added to the resulting solution and the mixture wasstirred for 2 hours. After addition of 10% sodium hydrogensulfate, theresulting mixture was extracted with ethyl acetate. The extract waswashed with water and brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure to give a residue. The resultingresidue was crystallized from ethanol to give the title compound (67 mg,75%) as needle crystals.

¹H-NMR(400 MHz,CDCl₃)δ: 2.69(2H,t,J=7.6 Hz), 2.96(2H,t,J=7.6 Hz),5.92(1H,s), 6.90(1H,m), 6.98(1H,m), 7.36(2H,d,J=8.4 Hz), 7.52(2H,d,J=8.4Hz), 7.56(2H,m), 7.99(1H,m), 8.47(1H,d,J=2.4 Hz).

mp: 158 to 160° C.

MSm/z: 452(M⁺+H).

Elemental Analysis for C₂₁H₁₆ClF₂NO₄S: Calculated: C, 55.82; H, 3.57; N,3.10; S, 7.10; Cl, 7.85; F, 8.41. Found: C, 55.70; H, 3.75; N, 3.19; S,7.12; Cl, 8.64; F, 8.11.

Example 47[6-[(4-Chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]carbaldehyde

To a 1,4-dioxane solution (30 ml) of the2-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]-5-(1,3-dioxolan-2-yl)pyridine(602 mg, 1.3 mmol) obtained in Example 42 was added 1N hydrochloric acid(30 ml). The resulting mixture was stirred at room temperature for 18hours. The reaction mixture was extracted with ethyl acetate. Theextract was washed with water, a saturated aqueous solution of sodiumbicarbonate and brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give a residue. The resultingresidue was purified by silica gel chromatography (hexane:ethylacetate=5:1) to give the title compound (530 mg, 98%) as needlecrystals.

¹H-NMR(400 MHz,CDCl₃)δ: 6.01(1H,s), 6.94(1H,m), 7.01(1H,m),7.40(2H,d,J=8.4 Hz), 7.54(2H,d,J=8.4 Hz), 7.81(1H,d,J=8.4 Hz),7.97(1H,m), 8.20(1H,dd,J=2.0,8.4 Hz), 9.05(1H,d,J=2.0 Hz), 10.12(1H,s).

Example 482-[(4-Chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]-5-(piperidin-1-ylmethyl)pyridine

To a methylene chloride solution (5 ml) of[6-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]carbaldehyde(82 mg, 0.2 mmol) and piperidine (40 μl, 0.4 mmol) were added aceticacid (23 μl, 0.4 mmol) and sodium triacetoxyborohydride (85 mg, 0.4mmol) at room temperature. The resulting mixture was stirred for 3hours. After the reaction was terminated by the addition of a saturatedaqueous solution of sodium bicarbonate, the reaction mixture was dilutedwith ethyl acetate (80 ml). The organic layer was collected byseparation, washed with water and brine, dried and concentrated underreduced pressure. The residue thus obtained was purified by silica gelchromatography (hexane:ethyl acetate=1:1), followed by crystallizationfrom ethanol to give the title compound (89 mg, 93%).

¹H-NMR(400 MHz,CDCl₃)δ: 1.5-1.6(6H,m), 2.3-2.4(4H,m), 3.45(2H,s),5.91(1H,s), 6.90(1H,m), 6.98(1H,m), 7.35(2H,d,J=8.4 Hz), 7.52(2H,d,J=8.4Hz), 7.53(1H,m), 7.7(1H,br), 8.02(1H,m), 8.49(1H,d,J=2.4 Hz).

mp: 113 to 114° C.

MSm/z: 477(M⁺+H).

Elemental Analysis for C₂₄H₂₃ClF₂N₂O₂S: Calculated: C, 60.44; H, 4.86;N, 5.87; S, 6.72; Cl, 7.43; F, 7.97. Found: C, 59.87; H, 4.81; N, 5.83;S, 6.87; Cl, 7.55; F, 8.02.

Example 494-[[6-[(4-Chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]morpholine

To a methylene chloride solution (5 ml) of the[6-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]carbaldehyde(82 mg, 0.2 mmol) obtained in Example 47 and morpholine (35 μl, 0.4mmol) were added acetic acid (23 μl, 0.4 mmol) and sodiumtriacetoxyborohydride (85 mg, 0.4 mmol) at room temperature. Theresulting mixture was stirred for 3 hours. After the reaction wasterminated by the addition of a saturated aqueous solution of sodiumbicarbonate, the reaction mixture was diluted with ethyl acetate (80ml). The organic layer was collected by separation, washed with waterand brine, dried and then concentrated under reduced pressure to give aresidue. The resulting residue was purified by silica gel chromatography(hexane:ethyl acetate=1:1), followed by crystallization from ethanol togive the title compound (90 mg, 94%).

¹H-NMR(400 MHz,CDCl₃)δ: 2.4(4H,m), 3.49(2H,s), 3.6(4H,m), 5.92(1H,s),6.90(1H,m), 6.98(1H,m), 7.36(2H,d,J=8.4 Hz), 7.53(2H,d,J=8.4 Hz),7.57(1H,d,J=8.0 Hz), 7.71(1H,br-d,J=8.0 Hz), 8.02(1H,m), 8.53(1H,d,J=2.0Hz).

mp: 120 to 121° C.

MSm/z: 479(M⁺+H).

Elemental Analysis for C₂₂H₂₁ClF₂N₂O₃S: Calculated: C, 57.68; H, 4.42;N, 5.85; S, 6.70; Cl, 7.40; F, 7.93. Found: C, 57.41; H, 4.43; N, 5.90;S, 6.82; Cl, 7.52; F, 7.91.

Example 50[6-[(4-Chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid

To a t-butanol solution (3.0 ml) of the[6-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]carbaldehyde(110 mg, 0.27 mmol) obtained in Example 47 was added 2-methyl-2-butene(143 μl, 1.35 mmol). An aqueous solution (0.6 ml) of sodiumdihydrogenphosphate (32.4 mg, 0.27 mmol) was added to the resultingsuspension. Sodium chlorite (98 mg, 1.08 mmol) was added further and themixture was stirred for 2 hours. To the reaction mixture were addedwater (30 ml) and acetic acid (1 ml). The resulting mixture wasextracted with ethyl acetate (100 ml). The extract was washed withbrine, dried and distilled under reduced pressure. The residue thusobtained was crystallized from ethanol to give the title compound (71mg, 62%) as colorless needle crystals.

¹H-NMR(400 MHz,CDCl₃)δ: 6.03(1H,s), 6.96(1H,m), 7.03(1H,m),7.42(2H,d,J=8.4 Hz), 7.56(2H,d,J=8.4 Hz), 7.73(1H,d,J=8.4 Hz),7.97(1H,m), 8.35(1H,dd,J=2.0,8.4 Hz), 9.20(1H,d,J=2.0 Hz).

mp: >230° C.

MSm/z: 424(M⁺+H).

Elemental Analysis for C₁₉H₁₂ClF₂NO₄S: Calculated: C, 53.84; H, 2.85; N,3.30; S, 7.57; Cl, 8.37; F, 8.97. Found: C, 53.47; H, 2.81; N, 3.46; S,7.65; Cl, 8.49; F, 9.00.

Example 513-[(4-Chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridine-N-oxide

To methylene chloride (15 ml) of the3-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridine (162 mg,0.427 mmol) obtained in Example 19 was added 3-chloroperbenzoic acid (81mg, 0.47 mmol). The resulting mixture was stirred for 24 hours. Thereaction mixture was diluted with ether (60 ml). The diluted mixture waswashed with a saturated aqueous solution of sodium bicarbonate, waterand brine, dried and filtered. The filtrate was concentrated underreduced pressure to give a residue. The resulting residue was subjectedto silica gel chromatography (ethyl acetate) to give the title compound(68 mg, 40%). The compound was crystallized from ethanol to affordcolorless needle crystals.

¹H-NMR(400 MHz,CDCl₃)δ: 5.58(1H,s), 6.95(1H,m), 7.03(1H,m),7.29(1H,dd,J=6.6,8.0 Hz), 7.42(2H,d,J=8.6 Hz), 7.57(1H,d,J=8.0 Hz),7.62(2H,d,J=8.4 Hz), 7.66(1H,m), 8.10(1H,d,J=6.6 Hz), 8.29(1H,s).

mp: 183 to 184° C.

Elemental Analysis for C₁₈H₁₂ClF₂NO₃S: Calculated: C, 54.62; H, 3.06; N,3.54; S, 8.10; Cl, 8.96; F, 9.60. Found: C, 54.19; H, 2.99; N, 3.67; S,8.27; Cl, 8.92; F, 9.53.

Example 524-[(4-Chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridine-N-oxide

To methylene chloride (20 ml) of the4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridine (221 mg,0.58 mmol) obtained in Example 20 was added 3-chloroperbenzoic acid (100mg, 0.58 mmol). The resulting mixture was stirred for 20 hours. Thereaction mixture was diluted with ether (60 ml). The diluted mixture waswashed with a saturated aqueous solution of sodium bicarbonate, waterand brine, dried and then filtered. The filtrate was concentrated underreduced pressure to afford a residue. The resulting residue wassubjected to silica gel chromatography (ethyl acetate) to give the titlecompound (183 mg, 80%). The compound was crystallized from ethanol toafford colorless needle crystals.

¹H-NMR(400 MHz,CDCl₃)δ: 5.62(1H,s), 6.97(1H,m), 7.06(1H,m),7.42(2H,d,J=7.2 Hz), 7.44(2H,d,J=8.8 Hz), 7.60(2H,d,J=8.8 Hz),7.68(1H,m), 8.17(2H,d,J=7.2 Hz).

mp: 211 to 212° C.

Elemental Analysis for C₁₈H₁₂ClF₂NO₃S: Calculated: C, 54.62; H, 3.06; N,3.54; S, 8.10; Cl, 8.96; F, 9.60. Found: C, 54.19; H, 2.92; N, 3.65; S,8.26; Cl, 8.99; F, 9.61.

Example 533-Chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine

The 3-chloro-4-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (511 mg, 2.0mmol) obtained in Referential Example 23 was dissolved in thionylchloride (3.0 ml). To the resulting solution was added a catalyticamount of dimethylformamide and the mixture was stirred for 17 hours.The reaction mixture was concentrated under reduced pressure. Toluenewas added to the residue, followed by further concentration.

The residue thus obtained was dissolved in dimethylformamide (10 ml). Tothe resulting solution were added 4-chlorobenzenethiol (375 mg, 2.6mmol) and potassium carbonate (414 mg, 3 mmol) under a nitrogenatmosphere. The resulting mixture was stirred at 60° C. for 3 hours.After the reaction mixture was cooled to room temperature, diethyl ether(60 ml) was added thereto. The resulting mixture was washed with waterand brine. The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure. The residue thus obtained wassubjected to silica gel chromatography (hexane:ethyl acetate=8:1) togive the title compound (196 mg, 26%) as a solid.

¹H-NMR(400 MHz,CDCl₃)δ: 6.07(1H,s), 6.95-7.08(2H,m), 7.18(1H,m),7.23(2H,d,J=8.8 Hz), 7.26(2H,d,J=8.8 Hz), 7.58(1H,d,J=5.2 Hz),8.51(1H,d,J=5.2 Hz), 8.58(1H,s).

mp: 70 to 72° C.

MSm/z: 382(M⁺+1).

Example 542,5-Dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine

The 2,5-dichloro-4-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (580 mg,2.0 mmol) obtained in Referential Example 24 was dissolved in thionylchloride (3.0 ml). To the resulting solution was added a catalyticamount of dimethylformamide. The resulting mixture was stirred for 17hours. The reaction mixture was concentrated under reduced pressure. Tothe residue was added toluene, followed by further concentration. Theresidue was dissolved in dimethylformamide (10 ml). To the resultingsolution were added 4-chlorobenzenethiol (375 mg, 2.6 mmol) andpotassium carbonate (414 mg, 3 mmol) under a nitrogen atmosphere. Theresulting mixture was stirred at 50° C. for 17 hours. After the reactionmixture was cooled to room temperature, diethyl ether (60 ml) was addedthereto. The resulting mixture was washed with water and brine. Theorganic layer was dried over magnesium sulfate and concentrated underreduced pressure. The residue thus obtained was subjected to silica gelchromatography (hexane:ether=10:1) to give the title compound (484 mg,58%) as a solid.

¹H-NMR(400 MHz,CDCl₃)δ: 5.96(1H,s), 6.95-7.04(2H,m), 7.01(1H,m),7.23(2H,d,J=8.8 Hz), 7.26(2H,d,J=8.8 Hz), 7.54(1H,s), 8.33(1H,s).

mp: 128 to 129° C.

MSm/z: 416(M⁺+1).

Example 553-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridine

To a methanol (12 ml) solution of the3-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(122 mg, 0.32 mmol) obtained in Example 53 was added hexaammoniumheptamolybdate tetrahydrate (60 mg), followed by the further addition of30% aqueous hydrogen peroxide (6 ml). The resulting mixture was stirredfor 24 hours. The reaction mixture was diluted with ethyl acetate. Thediluted solution was washed with water and brine, and concentrated underreduced pressure. The residue thus obtained was crystallized fromethanol to give the title compound (103 mg, 78%) as colorless needlecrystals.

¹H-NMR(400 MHz,CDCl₃)δ: 6.23(1H,s), 6.94(1H,m), 7.06(1H,m),7.41(2H,d,J=8.0 Hz), 7.53(1H,m), 7.59(2H,d,J=8.0 Hz), 8.11(1H,d,J=5.2Hz), 8.55(1H,s), 8.60(1H,d,J=5.2 Hz).

mp: 160 to 161° C.

Elemental Analysis for C₁₈H₁₁Cl₂F₂NO₂S: Calculated: C, 52.19; H, 2.68;N, 3.38; S, 7.74; Cl, 17.12; F, 9.17. Found: C, 52.17; H, 2.69; N, 3.44;S, 7.96; Cl, 17.12; F, 9.00.

Example 563-Chloro-4-[(4-chlorophenylsulfinyl)-(2,5-difluorophenyl)methyl]pyridine

To a methylene chloride (10 ml) solution of the3-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (75mg, 0.20 mmol) obtained in Example 53 was added 3-chloroperbenzoic acid(33 mg, 0.20 mmol). Under ice cooling, the resulting mixture was stirredfor 3 hours. After dilution with ether (80 ml), the diluted mixture waswashed with water and brine and concentrated under reduced pressure. Theresidue thus obtained was purified by silica gel chromatography(hexane:ethyl acetate=3:1) to give the title compound (48 mg, 60%) as adiastereomer mixture (1:1).

¹H-NMR(400 MHz,CDCl₃)δ: 5.53(½H,s), 5.66(½H,s), 6.83(½H,s), 6.95-7.08(3/2H,m), 7.23(½H,m), 7.25(1H,d,J=8.4 Hz), 7.26(1H,d,J=8.4 Hz),7.34(1H,d,J=8.4 Hz), 7.36(1H,d,J=8.4 Hz), 7.37(½H,m), 7.76(½H,d,J=5.2Hz), 7.98(½H,d,J=5.2 Hz), 8.47(½H,s), 8.56(½H,d,J=5.2 Hz), 8.60(½H,s),8.61(½H,d,J=5.2 Hz).

FAB-MS: 397.9992 (Calcd for C₁₈H₁₂Cl₂F₂NOS: 397.9985).

Example 572,5-Dichloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridine0.5 hydrate

To a methylene chloride (3.0 ml) solution of the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(60 mg, 0.14 mmol) obtained in Example 54 was added 3-chloroperbenzoicacid (62 mg, 0.36 mmol). The resulting mixture was stirred at roomtemperature for 3 hours. After dilution with ether (80 ml), the dilutedmixture was washed with a saturated aqueous solution of sodiumbicarbonate and brine, and concentrated under reduced pressure. Theresidue thus obtained was purified by silica gel chromatography(hexane:ethyl acetate=5:1) and crystallized from hexane to give thetitle compound (55 mg, 88%).

¹H-NMR(400 MHz,CDCl₃)δ: 6.15(1H,s), 6.93(1H,m), 7.05(1H,m),7.44(2H,d,J=8.8 Hz), 7.50(1H,m), 7.59(2H,d,J=8.8 Hz), 8.13(1H,s),8.55(1H,s), 8.33(1H,s).

mp: 147 to 148° C.

Elemental Analysis for C₁₈H₁₀Cl₃F₂NO₂S,0.5H₂O: Calculated: C, 47.23; H,2.42; N, 3.06; S, 7.01; Cl, 23.24; F, 8.30. Found: C, 47.25; H, 2.24; N,3.21; S, 7.19; Cl, 23.25; F, 8.32.

Example 584-[5-Chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]morpholine

A 1,4-dioxane (1.0 ml) solution of the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(100 mg, 0.24 mmol) obtained in Example 54 and morpholine (200 μl) wasstirred at 100° C. for 2 days under a nitrogen atmosphere. After coolingto room temperature, the reaction mixture was diluted with ethyl acetate(40 ml). The diluted mixture was washed with water and brine, dried andthen concentrated under reduced pressure to give a residue. Theresulting residue was purified by silica gel chromatography(hexane:ethyl acetate=5:1) to give the title compound (100 mg, 89%) asan oil.

¹H-NMR(400 MHz,CDCl₃)δ: 3.48(4H,m), 3.82(4H,m), 6.00(1H,s), 6.94(1H,s),6.94-7.04(2H,m), 7.09(1H,m), 7.23(2H,d,J=8.4 Hz), 7.24(2H,d,J=8.4 Hz),8.12(1H,s).

MSm/z: 467(M⁺+H).

Example 594-[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]morpholine

Hexaammonium heptamolybdate tetrahydrate (60 mg) was added to a methanol(12 ml) solution of4-[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]morpholine(90 mg, 0.19 mmol), followed by the further addition of 30% aqueoushydrogen peroxide (6 ml). The resulting mixture was stirred for 6 hours.The reaction mixture was diluted with ethyl acetate. The diluted mixturewas washed with water and brine and concentrated under reduced pressure.The residue thus obtained was subjected to silica gel chromatography(hexane:ethyl acetate=3:1) and crystallized from ethanol to give thetitle compound (80 mg, 83%) as colorless needle crystals.

¹H-NMR(400 MHz,CDCl₃)δ: 3.54(4H,m), 3.84(4H,m), 6.12(1H,s), 6.90(1H,m),7.02(1H,m), 7.42(2H,d,J=8.4 Hz), 7.45(1H,s), 7.46(1H,m), 7.58(2H,d,J=8.4Hz), 8.06(1H,s).

mp: 180 to 181° C.

Elemental Analysis for C₂₂H₁₈Cl₂F₂N₂O₃S: Calculated: C, 52.92; H, 3.63;N, 5.61; S, 6.42; Cl, 14.20; F, 7.61. Found: C, 52.68; H, 3.56; N, 5.69;S, 6.70; Cl, 14.32; F, 7.97.

Example 604-[2-[5-Chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]aminoethyl]morpholine

A 1,4-dioxane (1.0 ml) solution of the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(100 mg, 0.24 mmol) obtained in Example 54 and4-(2-aminoethyl)morpholine (200 μl) was stirred at 100° C. for 2 daysunder a nitrogen atmosphere. After cooling to room temperature, thereaction mixture was diluted with ethyl acetate (40 ml). The dilutedmixture was washed with water and brine, dried and concentrated underreduced pressure to give a residue. The resulting residue was purifiedby silica gel chromatography (3% methanol/chloroform) to give the titlecompound (12 mg, 10%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 2.42(4H,m), 2.54(2H,d,J=6.0 Hz), 3.27(2H,q,J=6.0Hz), 3.67(4H,m), 5.12(br,1H), 5.90(1H,s), 6.61(1H,s), 6.86-7.0(2H,m),7.06(1H,m), 7.15(2H,d,J=8.4 Hz), 7.16(2H,d,J=8.4 Hz), 7.95(1H,s).

MSm/z: 510(M⁺+H).

Example 614-[2-[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]aminoethyl]morpholine-N-oxide

Hexaammonium heptamolybdate tetrahydrate (10 mg) was added to a methanol(12 ml) solution of4-[2-[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]aminoethyl]morpholine(11 mg, 0.032 mmol), followed by the further addition of 30% aqueoushydrogen peroxide (1 ml). The resulting mixture was stirred for 8 hours.The reaction mixture was diluted with ethyl acetate. The diluted mixturewas washed with water and brine and concentrated under reduced pressure.The residue thus obtained was purified by silica gel chromatography (3%methanol, 3% t-butylamine/chloroform solution) to give the titlecompound (5.0 mg, 42%).

¹H-NMR(400 MHz,CDCl₃)δ: 3.2-3.4(4H,m), 3.54(2H,m), 3.81(2H,m),3.91(2H,m), 4.44(2H,m), 6.09(1H,s), 6.88(1H,m), 6.98(1H,m), 7.22(1H,s),7.40(2H,d,J=8.4 Hz), 7.51(1H,m), 7.60(2H,d,J=8.4 Hz), 7.94(1H,s).

FAB-MS: 558.0837 (Calcd for C₂₄H₂₄Cl₂F₂N₃O₄S: 558.0833).

Example 625-Azidomethyl-2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridine

The2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-(hydroxymethyl)pyridine(471 mg, 1.15 mmol) obtained in Example 43 was dissolved in a mixture ofcarbon tetrachloride (4 ml) and N,N-dimethylformamide (16 ml). To theresulting solution were added sodium azide (112 mg, 1.72 mmol) andtriphenylphosphine (451 mg, 1.72 mmol). The resulting mixture wasstirred at 90° C. for 3,hours. Water was added to the reaction mixture,followed by extraction with ethyl acetate. The organic layer was washedsequentially with water and brine. The resulting organic layer was driedover sodium sulfate and then concentrated under reduced pressure. Theresidue thus obtained was subjected to silica gel column chromatography.The fraction obtained from the hexane:ethyl acetate=3:1 eluate wasconcentrated under reduced pressure to give the title compound (244 mg,0.561 mmol, 49%) as a colorless amorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 4.42(2H,s), 5.96(1H,s), 6.94(1H,m),6.99-7.05(1H,m), 7.40(2H,d,J=8.8 Hz), 7.55(2H,d,J=8.8 Hz),7.60(1H,d,J=8.1 Hz), 7.72(1H,dd,J=8.1,2.0 Hz), 8.02(1H,m), 8.57(1H,d,J=2.0 Hz).

MSm/z: 435(M⁺+H).

Example 63[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine

Under an argon atmosphere,5-azidomethyl-2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridine(77 mg, 0.177 mmol), palladium carbon (14 mg), and ethyl acetate (2 ml)were added to ethanol (10 ml). The resulting mixture was stirred for 50minutes in a hydrogen atmosphere of 1 atmospheric pressure. The reactionmixture was filtered. The filtrate was concentrated under reducedpressure. The residue thus obtained was subjected to silica gel columnchromatography. A fraction obtained from thedichloromethane:methanol=10:1 eluate was concentrated under reducedpressure to give the title compound (28 mg, 0.0685 mmol, 39%) as a whitepowder.

¹H-NMR(400 MHz,CDCl₃)δ: 1.84(2H,brs), 3.92(2H,s), 5.94(1H,s),6.92(1H,m), 7.03-6.98(1H,m), 7.39(2H,d,J=8.3 Hz), 7.56(2H,d,J=8.3 Hz),7.60(1H,d,J=8.1 Hz), 7.74(1H,d,J=8.1 Hz), 8.01(1H,m), 8.57(1H,s).

MSm/z: 409(M⁺+H).

Example 64t-Butyl[[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]carbamate

The5-azidomethyl-2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridine(230 mg, 0.529 mmol) obtained in Example 62 and palladium carbon (46 mg)were added to a mixture of ethyl acetate (15 ml) and ethanol (15 ml).The resulting mixture was stirred for 45 minutes under a hydrogenatmosphere of 1 atmospheric pressure. The reaction mixture was filtered.The filtrate was then concentrated under reduced pressure. The residuethus obtained was dissolved in dichloromethane (5 ml). To the resultingsolution were added triethylamine (70 μl, 0.499 mmol) and di-t-butylcarbonate (174 mg, 0.996 mmol). The resulting mixture was stirred atroom temperature for 3 days. The reaction mixture was concentrated underreduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography, and the fraction obtained from thehexane:ethyl acetate=4:1 eluate was concentrated under reduced pressureto give the title compound (78 mg, 0.153 mmol, 37%) as a colorlessamorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 1.45(9H,s), 4.34(2H,d,J=5.6 Hz), 4.91(1H,brs),5.93(1H,s), 6.91(1H,m), 6.98-7.04(1H,m), 7.39(2H,d,J=8.8 Hz),7.54(2H,d,J=8.8 Hz), 7.59(1H,d,J=7.8 Hz), 7.67(1H,dd,J=7.8,2.2 Hz),7.99(1H,m), 8.53(1H,d,J=2.2 Hz).

MSm/z: 509(M⁺+H).

Example 65t-Butyl[[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-N-(t-butoxycarbonyl)carbamate

Under a nitrogen atmosphere, diisopropyl azodicarboxylate (128 μl, 0.653mmol) was added to a tetrahydrofuran (5 ml) solution of the2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-(hydroxymethyl)pyridine(178 mg, 0.435 mmol) obtained in Example 43, di-t-butyliminodicarboxylate (142 mg, 0.653 mmol) and triphenylphosphine (171 mg,0.653 mmol). The resulting mixture was stirred at room temperature for 5hours. Water was added to the reaction mixture, followed by extractionwith ethyl acetate. The organic layer was washed sequentially with waterand brine. The resulting organic layer was dried over sodium sulfate andthen, concentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel column chromatography, and the fractionobtained from the hexane:ethyl acetate=4:1 eluate was concentrated underreduced pressure to give the title compound (78 mg, 0.128 mmol, 32%) asa colorless oil.

¹H-NMR(400 MHz,CDCl₃)δ: 1.48(18H,s), 4.78(2H,s), 5.94(1H,s),6.93(1H,td,J=9.0,4.4 Hz), 6.98-7.04(1H,m), 7.38(2H,d,J=8.6 Hz),7.56(2H,d,J=8.6 Hz), 7.58(1H,d,J=8.1 Hz), 7.71(1H,dd,J=8.1,2.4 Hz),7.96-8.00(1H,m), 8.57 (1H,d, J=2.4 Hz).

MSm/z: 609(M⁺+H).

Example 66[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylaminehydrochloride

To an ethanol (2 ml) solution oft-butyl[[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-N-(t-butoxycarbonyl)carbamate(70 mg, 0.115 mmol) was added concentrated hydrochloric acid (2 ml). Theresulting mixture was stirred at room temperature for 3 hours. Thereaction mixture was concentrated under reduced pressure. To the residuethus obtained was added ethanol. The resulting mixture was concentratedunder reduced pressure to give the title compound (51 mg, 0.115 mmol,100%) as a white powder.

¹H-NMR(400 MHz,CD₃OD)δ: 4.18(2H,s), 6.22(1H,s), 7.03(1H,td,J=9.3,4.4Hz), 7.11-7.17(1H,m), 7.52(2H,d,J=8.8 Hz), 7.64(2H,d,J=8.8 Hz),7.79(1H,d,J=8.3 Hz), 7.92(1H,dd,J=8.3,2.2 Hz), 8.05-8.09(1H,m),8.71(1H,d,J=2.2 Hz)

Elemental Analysis for C₂₀H₁₅ClF₂N₂O₂S.HCl: Calculated: C, 51.25; H,3.62; Cl, 15.92; F, 8.53; N, 6.29. Found: C, 51.11; H, 3.57; Cl, 15.50;F, 8.39; N, 5.83.

Example 67N-acetyl-N-[[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]acetamide(Compound A) andN-[[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]acetamide(Compound B)

To a dichloromethane (3 ml) solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine(40 mg, 0.0978 mmol) obtained in Example 63 were addedN-methylmorpholine (26 μl, 0.234 mmol) and acetyl chloride (16 μl, 0.234mmol) under ice cooling. The resulting mixture was stirred at roomtemperature for 16 hours. Water was added to the reaction mixture,followed by extraction with ethyl acetate. The organic layer was washedsequentially with water and brine. The resulting organic layer was driedover sodium sulfate and concentrated under reduced pressure. The residuethus obtained was subjected to flash silica gel column chromatography.The fraction obtained from the hexane:ethyl acetate=2:3 eluate wasconcentrated under reduced pressure to give the title compound A (lowpolar compound) (15 mg, 0.0304 mmol, 40%) as a white power and the titleCompound B (high polar compound) (12 mg, 0.0266 mmol, 27%) as a whitepowder.

Compound A

¹H-NMR(400 MHz,CDCl₃)δ: 2.43(6H,s), 4.96(2H,s), 5.93(1H,s), 6.91(1H,m),6.98-7.03(1H,m), 7.39(2H,d,J=8.5 Hz), 7.54-7.61(2H,m), 7.55(2H,d,J=8.5Hz), 8.02(1H,m), 8.51 (1H,d,J=1.7 Hz).

mp: 60 to 64° C.

MSm/z: 493(M⁺+H).

Compound B

¹H-NMR(400 MHz,CDCl₃)δ: 2.03 and 2.04(3H,rotamers), 4.42-4.50(2H,m),5.89(1H,brs), 5.93(1H,s), 6.92(1H,td,J=9.1,4.4 Hz), 6.97-7.02(1H,m),7.41(2H,d,J=8.1 Hz), 7.57(2H,d,J=8.1 Hz), 7.61(1H,d,J=8.1 Hz),7.71(1H,d,J=8.1 Hz), 7.98-8.03(1H,m), 8.54(1H,s).

mp: 177 to 178° C.

MSm/z: 451(M⁺+H).

Example 68N-[[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-N′,N′-dimethylsulfamide

To a dichloromethane (5 ml) solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylaminehydrochloride (60 mg, 0.135 mmol) obtained in Example 66 were addedN-methylmorpholine (180 μl, 1.62 mmol), 4-dimethylaminopyridine (10 mg,0.0819 mmol) and N,N-dimethylsulfamoyl chloride (66 μl, 0.609 mmol). Theresulting mixture was stirred at room temperature for 24 hours. Waterwas added to the reaction mixture, followed by extraction withdichloromethane. The organic layer was washed sequentially with asaturated aqueous solution of sodium bicarbonate and brine. The organiclayer thus obtained was dried over magnesium sulfate and concentratedunder reduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=3:2 eluate was concentrated under reduced pressureto give the title compound (48 mg, 0.0930 mmol, 70%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 2.76(6H,s), 4.29(2H,d,J=6.4 Hz), 4.43(1H,t,J=6.4Hz), 5.94(1H,s), 6.92(1H,m), 6.98-7.04(1H,m), 7.41(2H,d,J=8.6 Hz),7.58(2H,d,J=8.6 Hz), 7.66(1H,d,J=8.1 Hz), 7.79(1H,dd,J=8.1,2.5 Hz),8.02(1H,m), 8.61 (1H,d,J=2.5 Hz)

mp: 177 to 178(C.

MSm/z: 516(M⁺+H).

Example 69 Ethyl2-[[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamino]-2-oxoacetate

To a dichloromethane (4 ml) solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine(30 mg, 0.0734 mmol) obtained in Example 63 were addedN-methylmorpholine (10 μl, 0.0881 mmol) and ethyl chloroglyoxylate (9μl, 0.0807 mmol) under ice cooling. The resulting mixture was stirred atroom temperature for 1 hour. Water was added to the reaction mixture,followed by extraction with dichloromethane. The organic layer was thensequentially washed with a saturated aqueous solution of sodiumbicarbonate and brine. The resulting organic layer was dried overmagnesium sulfate and concentrated under reduced pressure. The residuethus obtained was subjected to flash silica gel column chromatography.The fraction obtained from the hexane:ethyl acetate=3:2 eluate wasconcentrated under reduced pressure to give the title compound (28 mg,0.0550 mmol, 76%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 1.39(3H,t,J=7.1 Hz), 4.37(2H,q,J=7.1 Hz),4.55(2H,d,J=5.9 Hz), 5.94(1H,s), 6.89-6.94(1H,m), 6.98-7.05(1H,m),7.40(2H,d,J=8.3 Hz), 7.56(2H,d,J=8.3 Hz), 7.53(1H,brs), 7.62(1H,d,J=8.1Hz), 7.72(1H,d,J=8.1 Hz), 7.97-8.03(1H,m), 8.58(1H,s).

mp: 193 to 194° C.

MSm/z: 509(M⁺+H).

Example 70N-[[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-2-(4-methylphenylsulfonylamino)acetamide

To a dichloromethane (6 ml) solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylaminehydrochloride (40 mg, 0.0898 mmol) obtained in Example 66 were addedtriethylamine (45 μl, 0.324 mmol), 4-dimethylaminopyridine (5 mg, 0.0449mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21mg, 0.108 mmol) and N-p-tosylglycine (25 mg, 0.108 mmol). The resultingmixture was stirred at room temperature for 16 hours. The reactionmixture was diluted with dichloromethane. The diluted mixture was thenwashed sequentially with water, a saturated aqueous solution of sodiumbicarbonate and brine. The organic layer thus obtained was dried overmagnesium sulfate and then, concentrated under reduced pressure. Theresidue thus obtained was subjected to flash silica gel columnchromatography. The fraction obtained from the hexane:ethyl acetate=2.3eluate was concentrated under reduced pressure to give the titlecompound (41 mg, 0.0661 mmol, 73%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 2.44(3H,s), 3.59(2H,d,J=6.4 Hz),4.44(2H,dd,J=6.1,2.8 Hz), 5.42(1H,t,J=6.1 Hz), 5.95(1H,s), 6.91(1H,m),6.96-7.03(2H,m), 7.33(2H,d,J=8.3 Hz), 7.41(2H,d,J=8.6 Hz),7.57(2H,d,J=8.6 Hz), 7.58(1H,d,J=8.1 Hz), 7.66(1H,dd,J=8.1,2.4 Hz),7.74(2H,d,J=8.3 Hz), 8.01(1H,m), 8.49(1H,d,J=2.4 Hz).

mp: 217 to 218° C.

MSm/z: 620(M⁺+H).

Example 71N-[[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-2-dimethylaminoacetamide

To a dichloromethane (5 ml) solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine(30 mg, 0.0734 mmol) obtained in Example 63 were added triethylamine (12μl, 0.0881 mmol), 4-dimethylaminopyridine (5 mg, 0.0367 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (17 mg,0.0881 mmol) and N,N-dimethylglycine (9 mg, 0.0881 mmol). The resultingmixture was stirred at room temperature for 14 hours. The reactionmixture was diluted with dichloromethane. The diluted mixture was washedsequentially with water, a saturated aqueous solution of sodiumbicarbonate and brine. The organic layer thus obtained was dried overmagnesium sulfate and then, concentrated under reduced pressure. Theresidue thus obtained was subjected to flash silica gel columnchromatography. The fraction obtained from the hexane:ethyl acetate=1:4eluate was concentrated under reduced pressure to give the titlecompound (21 mg, 0.0425 mmol, 58%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 2.30(6H,s), 3.01(2H,s), 4.50(2H,d,J=6.1 Hz),5.93(1H,s), 6.91(1H,m), 6.98-7.04(1H,m), 7.40(2H,d,J=8.6 Hz),7.55(2H,d,J=8.6 Hz), 7.60(1H,d,J=8.1 Hz), 7.62(1H,brs),7.69(1H,dd,J=8.1,2.4 Hz), 8.02(1H,m), 8.56(1H,d, J=2.4 Hz).

mp: 177 to 179° C.

MSm/z: 494(M⁺+H).

Example 72N-[[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-4-(formylmethylamino)benzamide

To a dichloromethane (5 ml) solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine(50 mg, 0.122 mmol) obtained in Example 63 were added triethylamine (21μl, 0.147 mmol), 4-dimethylaminopyridine (7 mg, 0.0610 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (28 mg,0.147 mmol) and N-formyl-4-(methylamino)benzoic acid (26 mg, 0.147mmol). The resulting mixture was stirred at room temperature for 2hours. The reaction mixture was diluted with dichloromethane. Thediluted mixture was washed sequentially with water, a saturated aqueoussolution of sodium bicarbonate and brine. The organic layer thusobtained was dried over magnesium sulfate, and then concentrated underreduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=3:7 eluate was concentrated under reduced pressureto give the title compound (60 mg, 0.105 mmol, 87%) as a colorlessamorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 3.35(3H,s), 4.67-4.71(2H,m), 5.94(1H,s),6.53(1H,brs), 6.90(1H,m), 6.97-7.03(1H,m), 7.25(2H,d,J=8.6 Hz),7.40(2H,d,J=8.6 Hz), 7.56(2H,d,J=8.6 Hz), 7.63(1H,d,J=8.1 Hz),7.78(1H,dd,J=8.1,2.2 Hz), 7.86(2H,d,J=8.6 Hz), 8.03(1H,m), 8.61(1H,s),8.64 (1H,d,J=2.2 Hz).

MSm/z: 570(M⁺+H).

Example 73N-[[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-4-(methylthioformylamino)thiobenzamide

Under an argon atmosphere, a Lawson reagent (69 mg, 0.169 mmol) wasadded to a toluene (5 ml) solution ofN-[[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-4-(formylmethylamino)benzamide(46 mg, 0.0807 mmol). The resulting mixture was heated under reflux for12 hours. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate=4:1 eluate was concentrated underreduced pressure to give the title compound (40 mg, 0.0664 mmol, 83%) asa yellow amorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 3.72(3H,s), 5.08(2H,d,J=4.4 Hz), 5.92(1H,s),6.89(1H,td,J=9.0,4.4 Hz), 6.98-7.05(1H,m), 7.25(2H,d,J=8.6 Hz),7.40(2H,d,J=8.6 Hz), 7.55(2H,d,J=8.6 Hz), 7.60(1H,d,J=8.1 Hz),7.81(1H,d,J=8.1 Hz), 7.87(2H,d,J=8.6 Hz), 8.02-8.06(1H,m), 8.20(1H,brs),8.62(1H,s), 9.70(1H,s).

MSm/z: 602 (M⁺+H)

Example 74N-[[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-2-(pyridin-3-yl)acetamide

The[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine(30 mg, 0.073 mmol) obtained in Example 63, 3-pyridylacetic acidhydrochloride (16 mg, 0.092 mmol), 4-(dimethylamino)pyridine (5 mg, 0.04mmol) and triethylamine (0.025 ml, 0.18 mmol) were dissolved indichloromethane (5 ml). To the resulting solution was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (17 mg,0.089 mmol) at room temperature. The resulting mixture was stirred atroom temperature for 14 hours. To the reaction mixture was added asaturated aqueous solution (0.1 ml) of sodium bicarbonate. The residueobtained by concentrating the reaction mixture under reduced pressurewas subjected to flash silica gel chromatography. The fraction obtainedfrom the dichloromethane:methanol=30:1 elute was concentrated underreduced pressure to afford a white solid. The resulting solid was washedwith ether to give the title compound (35 mg, 0.066 mmol, 90%) as awhite powder.

¹H-NMR(400 MHz,CDCl₃)δ: 3.59(2H,s), 4.45(2H,dd,J=5.9,1.5 Hz),5.92(1H,s), 5.96-6.10(1H,m), 6.86-6.98(1H,m), 6.99-7.05(1H,m),7.24-7.35(1H,m), 7.39(2H,d,J=8.8 Hz), 7.55-7.60(3H,m), 7.60-7.71(2H,m),7.96-8.06(1H,m), 8.50(2H,d,J=1.6 Hz), 8.55(1H,d,J=4.8,1.6 Hz).

MSm/z: 528(M⁺+H).

Example 75[6-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methyldimethylcarbamate

To a dichloromethane (0.3 ml) solution of the2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-(hydroxylmethyl)pyridine(20 mg, 0.049 mmol) obtained in Example 43 were added N-methylmorpholine(0.011 ml, 0.10 mmol) and p-nitrophenyl chloroformate (15 mg, 0.074mmol) sequentially at 0° C. The resulting mixture was stirred at roomtemperature for 30 minute. To the reaction mixture were then addedN-methylmorpholine (0.033 ml, 0.30 mmol) and p-nitrophenyl chloroformate(15 mg, 0.074 mmol) sequentially at 0° C. The resulting mixture wasstirred at room temperature for 30 minutes. After addition ofdimethylamine hydrochloride (20 mg, 0.25 mmol) to the reaction mixtureat 0° C. and stirring the mixture for 13 hours, the reaction mixture waswashed with a saturated aqueous solution of ammonium chloride. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure. The residue thusobtained was subjected to flash silica gel chromatography. The fractionobtained from the hexane:ethyl acetate=7:3 eluate was concentrated underreduced pressure. The solid thus obtained was washed with hexane andcollected by filtration to give the title compound (13 mg, 0.027 mmol,55%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 2.94(6H,s), 5.14(2H,s), 5.94(1H,s),6.87-7.07(2H,m), 7.39(2H,d,J=8.5 Hz), 7.55(2H,d,J=8.5 Hz),7.62(1H,d,J=7.8 Hz), 7.75(1H,dd,J=7.8,2.0 Hz), 7.99-8.07(1H,m),8.63(1H,d,J=2.0 Hz).

MSm/z: 481(M⁺+H).

Example 76[6-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methyl4-nitrophenyl carbonate

To a dichloromethane (0.5 ml) solution of the2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-(hydroxylmethyl)pyridine(41 mg, 0.10 mmol) obtained in Example 43 were added N-methylmorpholine(0.033 ml, 0.30 mmol) and 4-nitrophenyl chloroformate (40 mg, 0.20 mmol)sequentially at 0° C. The resulting mixture was stirred at roomtemperature for 1 hour. The reaction mixture was washed with water. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure. The residue thusobtained was subjected to flash silica gel chromatography. The fractionobtained from the hexane:ethyl acetate=4:1 eluate was concentrated underreduced pressure. The solid thus obtained was washed with hexane andcollected by filtration to give the title compound (52 mg, 0.090 mmol,90%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 5.33(2H,s), 5.97(1H,s), 6.87-6.95(1H,m),6.98-7.06(1H,m), 7.39(2H,d,J=9.0 Hz), 7.40(2H,d,J=8.5 Hz),7.57(2H,d,J=8.5 Hz), 7.71(1H,d,J=7.6 Hz), 7.85(1H,dd,J=7.6,2.0 Hz),7.97-8.05(1H,m), 8.29(2H,d,J=9.0 Hz), 8.72(1H,d,J=2.0 Hz).

MSm/z: 575(M⁺+H).

Example 77[6-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methylbenzylcarbamate

To a dichloromethane (1 ml) solution of[6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methyl4-nitrophenyl carbonate (51 mg, 0.089 mmol) were addedN-methylmorpholine (0.020 ml, 0.18 mmol) and benzylamine (0.012 ml, 0.11mmol) sequentially at 0° C. The resulting mixture was stirred at roomtemperature for 20 hours. The reaction mixture was washed with asaturated aqueous solution of ammonium chloride. The organic layer wasdried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel chromatography. The fraction obtained fromthe eluate of hexane:ethyl acetate=4:1 was concentrated under reducedpressure. The solid thus obtained was washed with diisopropyl ether andcollected by filtration to give the title compound (33 mg, 0.060 mmol,68%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 4.38(2H,brd,J=5.4 Hz), 5.06(1H,brs), 5.16(2H,s),5.94(1H,s), 6.87-7.04(2H,m), 7.22-7.38(5H,m), 7.39(2H,d,J=8.3 Hz),7.54(2H,d,J=8.3 Hz), 7.62(1H,d,J=8.3 Hz), 7.74(1H,d,J=8.3 Hz),7.96-8.03(1H,m), 8.61(1H,s).

MSm/z: 543(M⁺+H).

Example 78N-[[6-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methyl]-3-cyanobenzenesulfonamide

To a dichloromethane (0.5 ml) solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine(28 mg, 0.068 mmol) obtained in Example 63 were added N-methylmorpholine(0.015 ml, 0.14 mmol) and 3-cyanobenzenesulfonyl chloride (22 mg, 0.10mmol) sequentially at 0° C. The resulting mixture was stirred at roomtemperature for 6 hours. The reaction mixture was washed with 1Nhydrochloric acid. The organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated under reducedpressure. The residue thus obtained was subjected to flash silica gelchromatography. The fraction obtained from the hexane:ethyl acetate=7:3eluate was concentrated under reduced pressure. The solid thus obtainedwas washed with hexane and collected by filtration to give the titlecompound (23 mg, 0.040 mmol, 59%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 4.26(2H,d,J=6.4 Hz), 5.08(1H,t,J=6.4 Hz),5.91(1H,s), 6.86-7.06(2H,m), 7.40(2H,d,J=8.1 Hz), 7.55(2H,d,J=8.1 Hz),7.57-7.70(3H,m), 7.81(1H,d,J=7.4 Hz), 7.94-8.05(2H,m), 8.11(1H,s),8.46(1H,s).

MSm/z: 574(M⁺+H).

Example 79N-[[6-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methyl]-3-cyano-N-methylbenzenesulfonamide

To a tetrahydrofuran (0.5 ml) solution ofN-[[6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methyl]-3-cyanobenzenesulfonamide(21 mg, 0.037 mmol) were added methanol (0.003 ml, 0.073 mmol),triphenylphosphine (19 mg, 0.073 mmol) and diisopropyl azodicarboxylate(0.014 ml, 0.073 mmol) sequentially at 0° C. The resulting mixture wasstirred at room temperature for 2 hours. The reaction mixture wasconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel chromatography. The fraction obtained fromthe hexane:ethyl acetate=2:1 eluate was concentrated under reducedpressure to give the title compound (13 mg, 0.021 mmol, 58%) as a whitesolid.

¹H-NMR(400 MHz,CDCl₃)δ: 2.70(3H,s), 4.25(2H,d,J=6.4 Hz), 5.95(1H,s),6.87-7.05(2H,m), 7.40(2H,d,J=8.5 Hz), 7.56(2H,d,J=8.5 Hz),7.66(1H,d,J=8.1 Hz), 7.73(1H,t,J=7.8 Hz), 7.81(1H,dd,J=8.1,2.2 Hz),7.91(1H,d,J=7.8 Hz), 7.99-8.09(2H,m), 8.12(1H,s), 8.53(1H,t,J=2.2 Hz).

MSm/z: 588(M⁺+H).

Example 803-[[6-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methyl]-1,1-dimethylurea

To a dichloromethane (1 ml) solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine(31 mg, 0.076 mmol) obtained in Example 63 were added triethylamine(0.032 ml, 0.23 mmol) and N,N-dimethylcarbamoyl chloride (0.014 ml, 0.15mmol) sequentially at 0° C. The resulting mixture was stirred at roomtemperature for 17 hours. To the reaction mixture were addedtriethylamine (0.032 ml, 0.23 mmol) and N,N-dimethylcarbamoyl chloride(0.014 ml, 0.15 mmol) sequentially at 0° C. The resulting mixture wasstirred at room temperature for 29 hours. The reaction mixture waswashed with a saturated aqueous solution of sodium bicarbonate. Theorganic layer was dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure. The residue thusobtained was subjected to flash silica gel chromatography. The fractionobtained from the eluate of ethyl acetate was concentrated under reducedpressure. The solid thus obtained was washed with hexane and collectedby filtration to give the title compound (18 mg, 0.036 mmol, 48%) as awhite solid.

¹H-NMR(400 MHz,CDCl₃)δ: 2.93(6H,s), 4.44(2H,d,J=4.2 Hz), 4.76(1H,t,J=4.2Hz), 5.93(1H,s), 6.85-7.04(2H,m), 7.39(2H,d,J=8.3 Hz), 7.56(2H,d,J=8.3Hz), 7.58(1H,d,J=8.5 Hz), 7.74(1H,dd,J=8.5,2.0 Hz), 7.98-8.06(1H,m),8.57 (1H,d,J=2.0 Hz)

MSm/z: 480(M⁺+H).

Example 81Methyl[6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methylcarbamate

In a similar manner to Example 80, the title compound (16 mg, 0.034mmol, 42%) as a yellow solid by using the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine(34 mg, 0.082 mmol) obtained in Example 63 and methyl chlorocarbonate(0.019 ml, 0.25 mmol).

¹H-NMR(400 MHz,CDCl₃)δ: 3.71(3H,s), 4.40(2H,d,J=6.1 Hz), 5.07(1H,brs),5.93(1H,s), 6.87-7.04(2H,m), 7.39(2H,d,J=8.5 Hz), 7.55(2H,d,J=8.5 Hz),7.60(1H,d,J=7.8 Hz), 7.70(1H,d,J=7.8 Hz), 7.97-8.04(1H,m), 8.55(1H,s).

MSm/z: 467(M⁺+H).

Example 82N-[[6-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methyl]methanesulfonamide

In a similar manner to Example 80, the title compound (20 mg, 0.040mmol, 49%) as a white solid by using the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine(34 mg, 0.082 mmol) obtained in Example 63 and methanesulfonyl chloride(0.019 ml, 0.25 mmol).

¹H-NMR(400 MHz,CDCl₃)δ: 2.97(3H,s), 4.37(2H,d,J=6.1 Hz), 4.70(1H,brs),5.95(1H,s), 6.88-7.07(2H,m), 7.40(2H,d,J=8.3 Hz), 7.56(2H,d,J=8.3 Hz),7.65(1H,d,J=8.1 Hz), 7.80(1H,d,J=8.1 Hz), 7.97-8.07(1H,m), 8.61(1H,s).

MSm/z: 487(M⁺+H).

Example 83N-[[6-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methyl]-1-acetyl-4-piperidinecarboxamide

In a similar manner to Example 80, the title compound (24 mg, 0.043mmol, 52%) as a colorless foamy substance by using the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine(34 mg, 0.082 mmol) obtained in Example 63 and1-acetyl-4-piperidinecarbonyl chloride (56 mg, 0.25 mmol).

¹H-NMR(400 MHz,CDCl₃)δ: 1.58-1.79(2H,m), 1.82-1.95(2H,m), 2.09(3H,s),2.30-2.41(1H,m), 2.59-2.70(1H,m), 3.03-3.13(1H,m), 3.82-3.92(1H,m),4.41-4.53(2H,m), 4.55-4.63(1H,m), 5.90-5.98(2H,m), 6.85-6.94(1H,m),6.97-7.04(1H,m), 7.40(2H,d,J=8.5 Hz), 7.55(2H,d,J=8.5 Hz),7.60(1H,d,J=8.1 Hz), 7.66(1H,d,J=8.1 Hz), 7.98-8.05(1H,m), 8.53(1H,s).

MSm/z: 562 (M⁺+H).

Example 84[6-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methylmethylcarbonate

To a dichloromethane (2 ml) solution of the2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-(hydroxymethyl)pyridine(50 mg, 0.12 mmol) obtained in Example 43 were added pyridine (0.040 ml,0.49 mmol) and methyl chloroformate (0.019 ml, 0.24 mmol) sequentiallyat 0° C. The resulting mixture was stirred at room temperature for 1hour. To the reaction mixture was added methyl chloroformate (0.019 ml,0.24 mmol) at 0° C. The resulting mixture was stirred at roomtemperature for 5 hours. The reaction mixture was washed with 1Nhydrochloric acid. The organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated under reducedpressure. The residue thus obtained was subjected to flash silica gelchromatography. The fraction obtained from the hexane:ethyl acetate=4:1eluate was concentrated under reduced pressure. The solid thus obtainedwas washed with hexane and collected by filtration to give the titlecompound (50 mg, 0.11 mmol, 88%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 3.81(3H,s), 5.18(2H,s), 5.95(1H,s),6.89-7.04(2H,m), 7.40(2H,d,J=8.5 Hz), 7.55(2H,d,J=8.5 Hz),7.65(1H,d,J=8.1 Hz), 7.78(1H,dd,J=8.1,2.2 Hz), 7.97-8.03(1H,m),8.64(1H,d,J=2.2 Hz).

MSm/z: 468(M⁺+H).

Example 85[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carbaldehydeoxime (Isomer A and Isomer B)

To a dichloromethane (3 ml) solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carbaldehyde(100 mg, 0.25 mmol) obtained in Example 47 were added N-methylmorpholine(32 μl, 0.29 mmol) and hydroxylamine hydrochloride (26 mg, 0.36 mmol).The resulting mixture was stirred at room temperature for 3 days. Thereaction mixture was diluted with dichloromethane, washed sequentiallywith water, a saturated aqueous solution of sodium bicarbonate andbrine. The organic layer thus obtained was dried over magnesium sulfateand concentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate=3:2 eluate was concentrated underreduced pressure to give the title Isomer A (low polar compound) (79 mg,0.19 mmol, 72%) as a white powder and the title Isomer B (high polarcompound) (17 mg, 0.040 mmol, 17%) as a white powder.

Isomer A

¹H-NMR(400 MHz,CDCl₃)δ: 5.97(1H,s), 6.91-6.96(1H,m), 6.99-7.05(1H,m),7.40(2H,d,J=8.6 Hz), 7.56(2H,d,J=8.6 Hz), 7.66(1H,d,J=8.1 Hz),7.78(1H,s), 7.96-8.02(2H,m), 8.14(1H,s), 8.75(1H,d,J=1.7 Hz).

mp: 187 to 188° C.

MSm/z: 423(M⁺+H).

Isomer B

¹H-NMR(400 MHz,CDCl₃)δ: 5.98(1H,s), 6.91-6.97(1H,m), 7.00-7.06(1H,m),7.40(1H,s), 7.41(2H,d,J=8.6 Hz), 7.57(2H,d,J=8.6 Hz), 7.71(1H,d,J=8.3Hz), 7.90-8.02(2H,m), 8.41(1H,dd,J=8.3,2.1 Hz), 9.00(1H,s).

mp: 194 to 196° C.

MSm/z: 423(M⁺+H).

Example 866-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-N-cyclohexylmethylnicotinamide

To a dichloromethane (5 ml) solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (80 mg, 0.19 mmol) obtained in Example 50 were added triethylamine(32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23mmol) and aminomethylcyclohexane (30 μl, 0.23 mmol). The resultingmixture was stirred at room temperature for 4.5 hours. The reactionmixture was diluted with dichloromethane and washed sequentially withwater, a saturated aqueous solution of sodium bicarbonate and brine. Theorganic layer thus obtained was dried over magnesium sulfate andconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate=3:1 eluate was concentrated underreduced pressure to give the title compound (58 mg, 0.11 mmol, 59%) as awhite powder.

¹H-NMR(400 MHz,CDCl₃)δ: 0.95-1.80(11H,m), 3.32(2H,d,J=6.4 Hz),5.98(1H,s), 6.13-6.16(1H,m), 6.90-6.96(1H,m), 7.00-706(1H,m),7.40(2H,d,J=8.6 Hz), 7.55(2H,d,J=8.6 Hz), 7.69(1H,d,J=8.3 Hz),7.97-8.02(1H,m), 8.13(1H,dd,J=8.3,2.2 Hz), 8.94(1H,d,J=2.2 Hz).

MSm/z: 519(M⁺+H).

Example 876-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-N-(5-chloropyridin-2-yl)nicotinamide

To a dichloromethane (5 ml) solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (80 mg, 0.19 mmol) obtained in Example 50 were added triethylamine(32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23mmol) and 2-amino-5-chloropyridine (29 mg, 0.23 mmol). The resultingmixture was stirred at room temperature for 5 hours. The reactionmixture was diluted with dichloromethane and washed sequentially withwater, a saturated aqueous solution of sodium bicarbonate and brine. Theorganic layer thus obtained was dried over magnesium sulfate andconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate=3:1 eluate was concentrated underreduced pressure to give the title compound (27 mg, 0.051 mmol, 27%) asa white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 6.04(1H,s), 6.92-6.97(1H,m), 7.01-707(1H,m),7.42(2H,d,J=8.6 Hz), 7.57(2H,d,J=8.6 Hz), 7.75(1H,dd,J=9.1,2.4 Hz),7.80(1H,d,J=8.1 Hz), 7.97-8.01(1H,m), 8.26(1H,dd,J=8.1,2.2 Hz),8.28(1H,d,J=2.4 Hz)8.33(1H,d,J=9.1 Hz), 8.51(1H,s), 9.12 (1H,d,J=2.2 Hz)

MSm/z: 534 (M⁺+H).

Example 886-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]nicotinic acidN′,N′-dimethylhydrazide

To a dichloromethane (5 ml) solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (80 mg, 0.19 mmol) obtained in Example 50 were added triethylamine(32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23mmol) and 1,1-dimethylhydrazine (21 μl, 0.23 mmol). The resultingmixture was stirred at room temperature for 7 hours. The reactionmixture was diluted with dichloromethane. The diluted mixture was washedsequentially with water, a saturated aqueous solution of sodiumbicarbonate and brine. The organic layer thus obtained was dried overmagnesium sulfate and concentrated under reduced pressure. The residuethus obtained was subjected to flash silica gel column chromatography.The fraction obtained from the dichloromethane:methanol=50:1 eluate wasconcentrated under reduced pressure to give the title compound (60 mg,0.13 mmol, 68%) as a colorless amorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 2.57(0.9H,s), 2.72(5.1H,s), 5.98(1H,s),6.48(0.15H,s), 6.90-7.06(2.85H,m), 7.41(2H,d,J=8.6 Hz), 7.56(2H,d,J=8.6Hz), 7.68(1H,d,J=8.1 Hz), 7.97-8.04(1H,m), 8.13-8.17(1H,m),8.94(0.85H,s), 9.07(0.15H,s)

MSm/z: 466(M⁺+H).

Example 896-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]nicotinic acidN′-(furan-2-carbonyl)hydrazide

To a dichloromethane (5 ml) solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (80 mg, 0.19 mmol) obtained in Example 50 were added triethylamine(32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23mmol) and 2-furanhydrazide (29 mg, 0.23 mmol). The resulting mixture wasstirred at room temperature for 7.5 hours. The reaction mixture wasdiluted with dichloromethane. The diluted mixture was then washedsequentially with water, a saturated aqueous solution of sodiumbicarbonate and brine. The organic layer thus obtained was dried overmagnesium sulfate and concentrated under reduced pressure under reducedpressure. The residue thus obtained was subjected to flash silica gelcolumn chromatography. The fraction obtained from thedichloromethane:methanol=50:1 eluate was concentrated under reducedpressure. The solid thus obtained was recrystallized fromdichloromethane-hexane to give the title compound (58 mg, 0.11 mmol,58%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 6.01(0.7H,s), 6.02(0.3H,s),6.55(0.7H,dd,J=3.4,1.7 Hz), 6.91-6.96(1H,m), 6.99-7.04(1H,m),7.21(0.7H,d,J=3.4 Hz), 7.41(2H,d,J=8.6 Hz), 7.53(0.3H,dd,J=1.7,0.7 Hz),7.56-7.60(3H,m), 7.74(1H,d,J=8.3 Hz), 7.77(0.3H,d,J=8.8 Hz),7.95-7.99(1H,m), 8.15-8.19(1H,m), 8.99(0.3H,s), 9.03(1H,d,J=2.2 Hz),9.14(0.7H,brs), 9.67(0.7H,brs), 9.98(0.3H,brs).

MSm/z: 532(M⁺+H).

Example 90N-[[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-(E)-3-(pyridin-4-yl)acrylamide

To a dichloromethane (1 ml) solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine(41 mg, 0.10 mmol) obtained in Example 63, (E)-3-(pyridin-4-yl)acrylicacid (15 mg, 0.10 mmol), benzotriazol-1-ol (14 mg, 0.10 mmol) andN-methylmorpholine (0.011 ml, 0.10 mmol) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19 mg, 0.10mmol) at 0° C. The resulting mixture was stirred at room temperature for19 hours. The reaction mixture was washed with a saturated aqueoussolution of sodium bicarbonate. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentratedunder reduced pressure. The residue thus obtained was subjected to flashsilica gel chromatography. The fraction obtained from the ethyl acetateeluate was concentrated under reduced pressure. The solid thus obtainedwas washed with diethyl ether and collected by filtration to give thetitle compound (35 mg, 0.065 mmol, 65%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 4.53-4.66(2H,m), 5.93(1H,s), 6.09-6.17(1H,m),6.57(1H,d,J=15.6 Hz), 6.86-6.93(1H,m), 6.96-7.04(1H,m), 7.34(2H,d,J=5.9Hz), 7.40(2H,d,J=8.5 Hz), 7.56(2H,d,J=8.5 Hz), 7.60(1H,d,J=15.6 Hz),7.61(1H,d,J=8.1 Hz), 7.74(1H,dd,J=8.1,2.2 Hz), 7.99-8.06(1H,m),8.59(1H,d,J=2.2 Hz), 8.64(2H,d,J=5.9 Hz).

MSm/z: 540(M⁺+H).

Example 91[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl](thiomorpholin-4-yl)methanone

In a similar manner to Example 90, the title compound (240 mg, 0.47mmol, 94%) as a white solid by using the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (212 mg, 0.50 mmol) obtained in Example 50 and thiomorpholine(0.047 ml, 0.50 mmol).

¹H-NMR(400 MHz,CDCl₃)δ: 2.61(2H,brs), 2.74(2H,brs), 3.69(2H,brs),4.04(2H,brs), 5.97(1H,s), 6.88-6.95(1H,m), 6.98-7.06(1H,m),7.41(2H,d,J=8.5 Hz), 7.57(2H,d,J=8.5 Hz), 7.73(1H,d,J=8.1 Hz),7.79(1H,dd,J=8.1,2.2 Hz), 7.95-8.02(1H,m), 8.64(1H,d,J=2.2 Hz).

MSm/z: 509(M⁺+H).

Example 92[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl](1,1-dioxo-1λ⁶-thiomorpholin-4-yl)methanone(Compound A) and[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl](1-oxo-1λ⁴-thiomorpholin-4-yl)methanone(Compound B)

To a dichloromethane (3 ml) solution of[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl](thiomorpholin-4-yl)methanone(153 mg, 0.30 mmol) was added 3-chloroperbenzoic acid (96 mg, 0.36 mmol)under ice cooling. The resulting mixture was stirred at room temperature2 hours. The reaction mixture was diluted with dichloromethane andwashed sequentially with a 1N aqueous sodium hydroxide solution andbrine. The organic layer thus obtained was dried over magnesium sulfateand concentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate=1:2 eluate was concentrated underreduced pressure to give the title compound A (low polar compound) (81mg, 0.15 mmol, 50%) as a white powder, while the fraction obtained fromthe dichloromethane:methanol=10:1 eluate was concentrated under reducedpressure to give the title compound B (high polar compound) (73 mg, 0.14mmol, 46%) as a white powder.

Compound A

¹H-NMR(400 MHz,CDCl₃)δ: 3.10(4H,brs), 4.13(4H,brs), 5.99(1H,s),6.88-6.93(1H,m), 7.00-7.06(1H,m), 7.42(2H,d,J=8.5 Hz), 7.58(2H,d,J=8.5Hz), 7.79(1H,d,J=8.1 Hz), 7.86(1H,dd,J=8.1,1.7 Hz), 7.97-8.02(1H,m),8.71(1H,d,J=1.7 Hz).

MSm/z: 541(M⁺+H).

Compound B

¹H-NMR(400 MHz,CDCl₃)δ: 2.70-3.00(4H,m), 3.74(1H,brs), 4.10(2H,brs),4.63(1H,brs), 5.98(1H,s), 6.88-6.94(1H,m), 7.00-7.06(1H,m),7.42(2H,d,J=8.6 Hz), 7.58(2H,d,J=8.6 Hz), 7.77(1H,d,J=8.1 Hz),7.84(1H,dd,J=8.1,2.2 Hz), 7.98-8.02(1H,m), 8.70(1H,d,J=2.2 Hz).

MSm/z: 525(M⁺+H).

Example 93N-(3-Methylthiopropyl)-6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]nicotinamide

In a similar manner to Example 90, the title compound (238 mg, 0.47mmol, 93%) as a white solid by using the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (212 mg, 0.50 mmol) obtained in Example 50 and3-methylthiopropylamine (0.055 ml, 0.50 mmol).

¹H-NMR(400 MHz,CDCl₃)δ: 1.92-2.01(2H,m), 2.14(3H,s), 2.63(2H,t,J=6.8Hz), 3.58-3.64(2H,m), 5.99(1H,s), 6.57-6.64(1H,m), 6.90-6.97(1H,m),6.99-7.06(1H,m), 7.41(2H,d,J=8.5 Hz), 7.56(2H,d,J=8.5 Hz),7.71(1H,d,J=8.1 Hz), 7.96-8.03(1H,m), 8.16(1H,dd,J=8.1,2.2 Hz),8.96(1H,d,J=2.2 Hz).

MSm/z: 511(M⁺+H).

Example 94N-(3-Methylsulfonylpropyl)-6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]nicotinamide(Compound A) andN-(3-methylsulfinylpropyl)-6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]nicotinamide(Compound B)

To a dichloromethane (3 ml) solution ofN-(3-methylthiopropyl)-6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]nicotinamide(153 mg, 0.30 mmol) was added 3-chloroperbenzoic acid (purity: 65% orgreater) (96 mg, 0.36 mmol) at 0° C. The resulting mixture was stirredat room temperature for 3 hours. The reaction mixture was washed with a1N aqueous sodium hydroxide solution. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentratedunder reduced pressure. The residue thus obtained was subjected to flashsilica gel chromatography. The fraction obtained from the ethyl acetateeluate was concentrated under reduced pressure. The solid thus obtainedwas washed with diethyl ether and collected by filtration to afford thetitle Compound A (53 mg, 0.098 mmol, 32%) as a white solid. The fractionobtained from the dichloromethane:methanol=15:1 eluate was thenconcentrated under reduced pressure. The solid thus obtained was washedwith diethyl ether and collected by filtration to give the titlecompound B (68 mg, 0.13 mmol, 43%) as a white solid.

Compound A

¹H-NMR(400 MHz,CDCl₃)δ: 2.20-2.30(2H,m), 2.98(3H,s), 3.17(2H,t,J=6.8Hz), 3.65-3.72(2H,m), 5.99(1H,s), 6.82-6.88(1H,m), 6.90-6.97(1H,m),6.99-7.06(1H,m), 7.41(2H,d,J=8.5 Hz), 7.56(2H,d,J=8.5 Hz),7.72(1H,d,J=8.1 Hz), 7.96-8.02(1H,m), 8.16(1H,dd,J=8.1,2.2 Hz),9.00(1H,d,J=2.2 Hz).

MSm/z: 543(M⁺+H).

Compound B

¹H-NMR(400 MHz,CDCl₃)δ: 2.11-2.23(1H,m), 2.26-2.37(1H,m), 2.63(3H,s),2.78-2.86(1H,m), 2.92-3.00(1H,m), 3.51-3.61(1H,m), 3.66-3.75(1H,m),5.99(1H,s), 6.90-6.98(1H,m), 6.99-7.06(1H,m), 7.40(2H,d,J=8.5 Hz),7.55(2H,d,J=8.5 Hz), 7.69(1H,d,J=8.1 Hz), 7.88-8.01(2H,m),8.22(1H,dd,J=8.1,2.2 Hz), 9.08(1H,d,J=2.2 Hz).

MSm/z: 527(M⁺+H).

Example 952-Chloro-5-[(3-chloropyridin-4-yl)(2,5-difluorophenyl)methylthio]pyridine

To an ethanol (7 ml) solution of the O-ethyl S-(6-chloro-3-pyridyl)dithiocarbonate (164 mg, 0.70 mmol) obtained in Referential Example 26was added a 1N aqueous sodium hydroxide solution (7 ml). The resultingmixture was stirred at 80° C. for 3 hours. After the reaction mixturewas cooled to room temperature, 1N hydrochloric acid was added thereto.The resulting mixture was extracted with dichloromethane. The organiclayer was dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated under reduced pressure to afford6-chloro-3-pyridinethiol as a yellow solid.

To a dichloromethane (3 ml) solution of the3-chloro-4-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (153 mg, 0.60mmol) obtained in Referential Example 23 were added triethylamine (0.167ml, 1.20 mmol) and methanesulfonyl chloride (0.070 ml, 0.90 mmol)sequentially at 0° C. The resulting mixture was stirred at roomtemperature for 2 hours. The reaction mixture was washed with asaturated aqueous solution of sodium bicarbonate. The organic layer wasthen dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure. To an N,N-dimethylformamide (3 ml)solution of the residue thus obtained was added an N,N-dimethylformamide(2 ml) solution of 6-chloro-3-pyridinethiol and potassium carbonate (100mg, 0.72 mmol) sequentially. The resulting mixture was stirred at roomtemperature for 18 hours. Ethyl acetate was added to the reactionmixture. The resulting mixture was washed with a saturated aqueoussolution of sodium bicarbonate. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentratedunder reduced pressure. The residue thus obtained was subjected to flashsilica gel chromatography. The fraction obtained from the hexane:ethylacetate=17:3 eluate was concentrated under reduced pressure to give thetitle compound (111 mg, 0.29 mmol, 48%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 6.04(1H,s), 6.95-7.05(2H,m), 7.10-7.20(1H,m),7.25(1H,d,J=8.1 Hz), 7.57(1H,d,J=5.1 Hz), 7.60(1H,dd,J=8.1,2.5 Hz),8.31(1H,d,J=2.5 Hz), 8.54(1H,d,J=5.1 Hz), 8.59(1H,s).

MSm/z: 383(M⁺+H).

Example 962-Chloro-5-[(3-chloropyridin-4-yl)(2,5-difluorophenyl)methylsulfonyl]pyridine

To a methanol (4 ml) solution of2-chloro-5-[(3-chloropyridin-4-yl)(2,5-difluorophenyl)methylthio]pyridine(109 mg, 0.28 mmol) were added 31% aqueous hydrogen peroxide (2 ml) andhexaammonium heptamolybdate tetrahydrate (30 mg). The resulting mixturewas stirred at room temperature for 17 hours. Ethyl acetate was added tothe reaction mixture. The resulting mixture was washed with a saturatedaqueous solution of sodium bicarbonate. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentratedunder reduced pressure. The residue was subjected to flash silica gelcolumn chromatography. The fraction obtained from the hexane:ethylacetate=17:3 eluate was concentrated under reduced pressure to give thetitle compound (108 mg, 0.26 mmol, 92%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 6.26(1H,s), 6.94-7.03(1H,m), 7.06-7.15(1H,m),7.44(1H,d,J=8.3 Hz), 7.50-7.56(1H,m), 7.89(1H,dd,J=8.3,2.7 Hz),8.12(1H,d,J=5.1 Hz), 8.59(1H,d,J=2.7 Hz), 8.61(1H,s), 8.66(1H,d,J=5.1Hz).

MSm/z: 415(M⁺+H).

Example 975-[(3-Chloropyridin-4-yl)(2,5-difluorophenyl)methylsulfonyl]-2-fluoropyridine

To an acetonitrile (2 ml) solution of2-chloro-5-[(3-chloropyridin-4-yl)(2,5-difluorophenyl)methylsulfonyl]pyridine(66 mg, 0.16 mmol) were added potassium fluoride (94 mg, 1.60 mmol) andtetraphenylphosphonium bromide (134 mg, 0.32 mmol). The resultingmixture was heated under reflux for 16 hours. After the reaction mixturewas cooled to room temperature, dichloromethane was added thereto. Theresulting mixture was washed with water. The organic layer was driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure. The residue was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=17:3 eluate is concentrated under reduced pressureto give the title compound (4.5 mg, 0.011 mmol, 7%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 6.26(1H,s), 6.93-7.13(3H,m), 7.50-7.56(1H,m),8.01-8.08(1H,m), 8.13(1H,d,J=5.1 Hz), 8.48(1H,d,J=2.2 Hz), 8.60(1H,s),8.66(1H,d,J=5.1 Hz).

MSm/z: 440(M⁺+H+ MeCN).

Example 98N′-[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-ylmethylildene]-2-thiophenecarbohydrazide

The[6-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]carbaldehyde(100 mg, 0.245 mmol) obtained in Example 47 and2-thiophenecarbohydrazide (41.7 mg, 0.294 mmol) were dissolved inethanol (3 ml). The resulting mixture was stirred at room temperaturefor 3 days. The solid thus precipitated was collected by filtration andwashed with ethanol. The solid thus obtained was recrystallized fromethanol to give the title compound (91.0 mg, 0.171 mmol, 70%) as a whitesolid.

¹H-NMR(400 MHz,CDCl₃/DMSO-d₆)δ: 5.98(1H,s), 6.93-7.01(1H,m),7.02-7.09(1H,m), 7.14-7.20(1H,brm), 7.42(2H,d,J=8.5 Hz), 7.57(2H,d,J=8.5Hz), 7.62-7.73(2H,brm), 8.02-8.20(3H,m), 8.95(1H,s), 11.5(1H,s).

MSm/z: 532(M⁺+H).

Example 996-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]nicotinamide

To a dichloromethane (4 ml) suspension of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (100 mg, 0.236 mmol) obtained in Example 50 were added thionylchloride (1.00 ml) and N,N-dimethylformamide (one drop). The resultingmixture was stirred at room temperature for 18 hours. The reactionmixture was concentrated to dryness. The residue thus obtained wasdissolved in dichloromethane (6 ml). A 28% aqueous ammonia (2 ml) wasadded to the resulting solution. After the mixture was stirred at roomtemperature for 3 hours, the reaction mixture was acidified with 1Nhydrochloric acid. The resulting mixture was concentrated and the solidthus formed was collected by filtration. The solid thus obtained waswashed with water and ethanol and then, recrystallized from ethanol togive the title compound (47.9 mg, 0.113 mmol, 46%) as a white solid.

¹H-NMR(400 MHz,CDCl₃/DMSO-d₆)δ: 6.00(1H,s), 6.38(1H,brs),6.94-6.99(1H,m), 7.02-7.08(1H,m), 7.43(2H,d,J=8.5 Hz), 7.56(2H,d,J=8.5Hz), 7.67(1H,d,J=7.6 Hz), 7.65-7.75(1H,brm), 7.99-8.04(1H,m),8.26(1H,dd,J=8.1,2.4 Hz), 9.12(1H,d,J=1.7 Hz).

MSm/z: 423(M⁺+H).

Example 1006-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-N-(4-methylcyclohexyl)nicotinamide

To a dichloromethane (4 ml) suspension of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (100 mg, 0.236 mmol) obtained in Example 50 were added thionylchloride (1.00 ml) and N,N-dimethylformamide (one drop). The resultingmixture was stirred at room temperature for 6 hours. The reactionmixture was concentrated to dryness and the residue thus obtained wasdissolved in dichloromethane (6 ml). To the resulting solution wereadded N-methylmorpholine (51.8 μl, 0.472 mmol) and4-methylcyclohexylamine (37.4 μl, 0.283 mmol). The resulting mixture wasstirred at room temperature for 18 hours, followed by dilution withdichloromethane. The diluted mixture was washed sequentially with 1Nhydrochloric acid, water and brine, dried over magnesium sulfate andconcentrated. The residue thus obtained was subjected to flash silicagel column chromatography. The fraction obtained from the hexane:ethylacetate=3:1 eluate was concentrated to give a white solid. The solidthus obtained was recrystallized from ethyl acetate-hexane to give thetitle compound (70.3 mg, 0.135 mmol, 57%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 0.92(1.8H,d,J=6.6 Hz), 0.96(1.2H,d,J=6.4 Hz),1.05-1.30(3H,m), 1.32-1.43(0.6H,m), 1.55-1.83(4.4H,m), 2.03-2.12(1H,m),3.86-3.97(0.6H,m), 4.20-4.28(0.4H,m), 5.88(0.6H,d,J=7.1 Hz), 5.98(1H,s),6.18(0.4H,d,J=7.3 Hz), 6.90-6.96(1H,m), 6.98-7.06(1H,m),7.41(1.2H,d,J=8.1 Hz), 7.41(0.8H,d,J=8.1 Hz), 7.56(1.2H,d,J=8.1 Hz),7.57(0.8H,d,J=8.1 Hz), 7.67-7.72(1H,m), 7.97-8.05(1H,m),8.10-8.18(1H,m), 8.93(0.6H,d,J=2.2 Hz), 8.96(0.4H,d,J=2.2 Hz).

MSm/z: 519(M⁺+H).

Example 1016-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-N-methoxynicotinamide

To a dichloromethane (6 ml) suspension of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (100 mg, 0.236 mmol) obtained in Example 50 were addedN-methylmorpholine (77.7 μl, 0.708 mmol), O-methylhydroxylaminehydrochloride (23.6 mg, 0.283 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54.3 mg,0.283 mmol). The resulting mixture was stirred at room temperature for 1hour. To the reaction mixture was added tetrahydrofuran (1 ml). Afterstirring at room temperature for 18 hours, the reaction mixture wasdiluted with dichloromethane. The diluted mixture was washed with waterand brine. The organic layer thus obtained was dried over magnesiumsulfate and concentrated under reduced pressure. The residue thusobtained was subjected to flash silica gel column chromatography. Thefraction obtained from the hexane:ethyl acetate=1:1 eluate wasconcentrated to give a white solid. The resulting solid was washed withethyl acetate to give the title compound (55.1 mg, 0.122 mmol, 52%) as awhite powder.

¹H-NMR(400 MHz,CDCl₃)δ: 3.90(2.4H,s), 3.97(0.6H,s), 5.97(0.2H,s),5.98(0.8H,s), 6.90-7.07(2H,m), 7.39-7.46(2H,m), 7.54-7.59(2H,m),7.63(0.2H,d,J=8.3 Hz), 7.73(0.8H,d,J=8.1 Hz), 7.94-8.00(1H,m),8.10-8.15(1H,m), 8.76(1H,brs), 8.92(0.8H,d,J=1.7 Hz), 9.01(0.2H,d,J=1.5Hz).

MSm/z: 453(M⁺+H).

Example 102N,N-Dimethyl-[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine

The[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carbaldehyde(100 mg, 0.245 mmol) obtained in Example 47, a tetrahydrofuran solution(2.0M, 0.25 ml, 0.50 mmol) of dimethylamine and acetic acid (0.029 ml,0.51 mmol) were dissolved in 1,2-dichloroethane (5 ml), followed by theaddition of sodium triacetoxyborohydride (115 mg, 0.515 mmol) at roomtemperature. The resulting mixture was stirred at room temperature for 3days. To the reaction mixture were added a saturated aqueous solution ofsodium bicarbonate and ethyl acetate. The resulting mixture wasseparated into layers. The organic layer thus obtained was washedsequentially with a saturated aqueous solution of sodium bicarbonate andbrine, and dried over anhydrous magnesium sulfate. After filtration, thefiltrate was concentrated under reduced pressure. The residue thusobtained was subjected to flash silica gel chromatography. The fractionobtained from the dichloromethane:methanol=40:1 eluate was concentratedunder reduced pressure to yield a white solid. The resulting solid waswashed with hexane to give the title compound (88 mg, 0.20 mmol, 82%) asa white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 2.23(6H,s), 3.43(2H,s), 5.94(1H,s),6.88-6.98(1H,m), 6.98-7.06(1H,m), 7.38(2H,d,J=8.6 Hz), 7.52-7.62(3H,m),7.71(1H,dd,J=8.1,2.1 Hz), 7.98-8.08(1H,m), 8.51 (1H,d,J=2.1 Hz).

MSm/z: 437(M⁺+H).

Example 103N-[[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]bis(2-methoxyethyl)amine

The[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carbaldehyde(100 mg, 0.245 mmol) obtained in Example 47, bis(2-methoxyethyl)amine(70 mg, 0.53 mmol) and acetic acid (0.029 ml, 0.51 mmol) were dissolvedin 1,2-dichloroethane (5 ml). To the resulting solution was added sodiumtriacetoxyborohydride (115 mg, 0.515 mmol) at room temperature. Theresulting mixture was stirred at room temperature for 3 days. To thereaction mixture were added a saturated aqueous solution of sodiumbicarbonate and ethyl acetate. The resulting mixture was separated intolayers. The organic layer thus obtained was washed sequentially with asaturated aqueous solution of sodium bicarbonate and brine, and driedover anhydrous magnesium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel chromatography. The fraction obtained fromthe hexane:ethyl acetate=3:2 eluate was concentrated under reducedpressure to afford a white solid. The resulting solid was washed withhexane to give the title compound (101 mg, 0.192 mmol, 78%) as a whitepowder.

¹H-NMR(400 MHz,CDCl₃)δ: 2.73(4H,t,J=5.8 Hz), 3.31(6H,s), 3.47(4H,d,J=5.8Hz), 3.75(2H,s), 5.93(1H,s), 6.88-6.97(1H,m), 6.97-7.07(1H,m),7.38(2H,d,J=8.8 Hz), 7.50-7.60(3H,m), 7.76(1H,dd,J=8.1,2.0 Hz),7.98-8.08(1H,m), 8.54(1H,d,J=2.0 Hz).

MSm/z: 525(M⁺+H).

Example 1046-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-N,N-dimethylnicotinamide

The[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (90 mg, 0.21 mmol) obtained in Example 50, a tetrahydrofuransolution (2.0M, 0.21 ml, 0.42 mmol) of dimethylamine,4-(dimethylamino)pyridine (15 mg, 0.12 mmol) and triethylamine (0.045ml, 0.32 mmol) were dissolved in dichloromethane (5 ml). To theresulting solution was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.32mmol) at room temperature, followed by stirring at room temperature for14 hours. The residue obtained by concentrating the reaction mixtureunder reduced pressure was subjected to flash silica gel chromatography.The fraction obtained from the hexane:ethyl acetate=2:1 eluate wasconcentrated under reduced pressure to give the title compound (35 mg,0.066 mmol, 90%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 3.01(3H,s), 3.14(3H,s), 5.97(1H,s),6.88-6.99(1H,m), 6.99-7.08(1H,m), 7.40(2H,d,J=8.7 Hz), 7.57(2H,d,J=8.7Hz), 7.70(1H,dd,J=8.0,0.7 Hz), 7.82(1H,dd,J=8.0,2.2 Hz),7.93-8.04(1H,m), 8.68(1H,dd,J=2.2,0.7 Hz).

MSm/z: 451(M⁺+H).

Example 105[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl](4-methylpiperazin-1-yl)methanone

The[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (90 mg, 0.21 mmol) obtained in Example 50, N-methylpiperazine(0.036 ml, 0.33 mmol), 4-(dimethylamino)pyridine (15 mg, 0.12 mmol) andtriethylamine (0.045 ml, 0.32 mmol) were dissolved in dichloromethane (5ml). To the resulting solution was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.32mmol) at room temperature. The resulting mixture was stirred at roomtemperature for 14 hours. To the reaction mixture were addedN-methylpiperazine (0.036 ml, 0.33 mmol), triethylamine (0.045 ml, 0.32mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(61 mg, 0.32 mmol). The resulting mixture was stirred at roomtemperature for 14 hours. The reaction mixture was then concentratedunder reduced pressure. The residue thus obtained was subjected to flashsilica gel chromatography. The fraction obtained from thedichloromethane:methanol=25:1 eluate was concentrated under reducedpressure to afford the title compound (86 mg, 0.17 mmol, 80%) as a whitepowder.

¹H-NMR(400 MHz,CDCl₃)δ: 2.33(3H,s), 2.38(2H,brs), 2.50(2H,brs),3.44(2H,brs), 3.81(2H,brs), 5.97(1H,s), 6.87-6.98(1H,m),6.98-7.08(1H,m), 7.40(2H,d,J=8.8 Hz), 7.57(2H,d,J=8.8 Hz),7.71(1H,dd,J=8.1,0.7 Hz), 7.81(1H,dd,J=8.1,2.2 Hz), 7.94-8.04(1H,m),8.66(1H,dd,J=2.2,0.7 Hz).

MSm/z: 506(M⁺+H).

Example 1064-[2-[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]aminoethyl]morpholine

The4-[2-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]aminoethyl]morpholine-N-oxide(78 mg, 0.14 mmol) obtained in Example 61 was dissolved in a mixedsolvent of acetic acid (2.0 ml) and water (2.0 ml). The resultingsolution was heated to 60° C. and iron powder (40 mg, 0.72 mmol) wasadded thereto. The resulting mixture was stirred for 30 minutes. Aftercooling, the reaction mixture was poured into a saturated aqueoussolution of potassium carbonate, followed by extraction with ethylacetate (60 ml). The extract was washed with brine, dried andconcentrated under reduced pressure. The residue thus obtained waspurified by silica gel chromatography (3% methanol/chloroform solution)to give the title compound (30 mg, 40%).

¹H-NMR(400 MHz,CDCl₃)δ: 2.5-2.8(6H,m), 3.59(2H,br), 3.81(4H,br),5.45(1H,br), 6.10(1H,s), 6.88(1H,m), 7.01(1H,m), 7.25(1H,s),7.42(2H,d,J=8.8 Hz), 7.49(1H,m), 7.60(2H,d,J=8.4 Hz), 7.97(1H,s).

MSm/z: 542(M⁺+H).

Example 107 t-Butyl2-[N-[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]-N-methylamino]ethyl-methylcarbamate

A 1,4-dioxane (2.0 ml) solution of the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(78 mg, 0.19 mmol) obtained in Example 54 andN,N′-dimethylethylenediamine (400 μl) were stirred at 100° C. for 2 daysunder a nitrogen atmosphere. After cooling to room temperature, thereaction mixture was diluted with ethyl acetate (40 ml). The dilutedmixture was washed with water and brine, dried and then concentratedunder reduced pressure to give a residue. The residue thus obtained wasdissolved in tetrahydrofuran (10 ml). To the resulting solution wereadded triethylamine (31 μl, 0.22 mmol) and di-t-butyl dicarbonate (49mg, 0.22 mmol) at room temperature. The resulting mixture was stirredfor 15-hours. The reaction mixture was concentrated under reducedpressure. The residue thus obtained was purified by silica gelchromatography (hexane:ethyl acetate=4:1) to give the title compound (68mg, 64%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 1.26 and 1.32(9H,br-s,rotamer), 2.75 and2.78(3H,br-s,rotamer), 2.95(3H,br-s), 3.30(2H,m), 3.65(2H,m),5.92(1H,s), 6.6-6.8(1H,m), 6.84-6.97(2H,m), 7.05(1H,m), 7.14(2H,d,J=8.8Hz), 7.17(2H,d,J=8.4 Hz), 7.98(1H,s).

MSm/z: 568(M⁺+H).

Example 108 t-Butyl2-[N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]-N-methylamino]ethyl-methylcarbamate

To a methanol (6 ml) solution of t-butyl2-[N-[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]-N-methylamino]ethylmethylcarbamate(67 mg, 0.12 mmol) were added hexaammonium heptamolybdate tetrahydrate(30 mg), followed by the further addition of 30% aqueous hydrogenperoxide (3 ml). The resulting mixture was stirred for 17 hours. Afterthe reaction mixture was diluted with ethyl acetate, the diluted mixturewas washed with water and brine, and then concentrated under reducedpressure. The residue thus obtained was purified by silica gelchromatography (hexane:ethyl acetate=3:1) to give the title compound (64mg, 91%).

¹H-NMR(400 MHz,CDCl₃)δ: 1.33 and 1.38(9H,br-s,rotamer), 2.87 and2.89(3H,br-s,rotamer), 3.11(3H,br-s), 3.3-3.4(2H,m), 3.6-3.9(2H,m),6.12(1H,s), 6.89(1H,m), 7.00(1H,m), 7.26(1H,m), 7.41(2H,d,J=8.4 Hz),7.53(1H,m), 7.59(2H,d,J=8.4 Hz), 8.00(1H,s).

EI-MS: 599.1204 (Calcd for C₂₇H₂₉Cl₂F₂N₃O₄S: 599.1224).

Example 1095-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]-2-[N-methyl-N-[2-(methylamino)ethyl]amino]pyridine

In methylene chloride (2.0 ml) was dissolved t-butyl2-[N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]-N-methylamino]ethylmethylcarbamate(61 mg, 0.10 mmol). To the resulting solution were added anisole (40 μl)and trifluoroacetic acid (200 μl) at room temperature and the resultingmixture was stirred for 1 hour. The residue obtained by concentratingthe reaction mixture under reduced pressure was purified by silica gelchromatography (3% methanol/chloroform 3%→methanol, 3%t-butylamine/chloroform) to give the title compound (21 mg, 41%) as anoil.

¹H-NMR(400 MHz,CDCl₃)δ: 2.51(3H,s), 2.90(2H,d,J=6.0 Hz), 3.14(3H,s),3.72(2H,m), 6.13(1H,s), 6.89(1H,m), 7.00(1H,m), 7.36(1H,m),7.41(2H,d,J=8.4 Hz), 7.52(1H,m), 7.60(2H,d,J=8.4 Hz), 8.00(1H,s).

FAB-MS: 500.0770 (Calcd for C₂₂H₂₂Cl₂F₂N₃O₂S: 500.0778).

Example 110(2′S)-5-Chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]-2-[2′-(hydroxymethyl)pyrrolidin-1′-yl]pyridine

A 1,4-dioxane (1.0 ml) solution of the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(60 mg, 0.14 mmol) obtained in Example 54 and (S)-2-pyrrolidinemethanol(200 μl) was stirred at 100° C. for 3 days under a nitrogen atmosphere.After cooling to room temperature, the reaction mixture was diluted withethyl acetate (50 ml). The diluted mixture was washed with water andbrine, dried and then concentrated under reduced pressure. The residuethus obtained was purified by silica gel chromatography (hexane:ethylacetate=5:1) to give the title compound (40 mg, 58%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 1.78(1H,m), 2.06(3H,m), 3.29(1H,m), 3.50(1H,m),3.66(1H,m), 3.72(1H,m), 4.33(1H,m), 5.97 and 5.98(1H,s,rotamer), 6.73and 6.77(1H,s,rotamer), 6.92-7.15(3H,m), 7.25(4H,m), 7.98(1H,s).

MSm/z: 481(M⁺+H).

Example 111(2′S)-5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl-2-[2′-(hydroxymethyl)pyrrolidin-1′-yl]pyridine

Hexaammonium heptamolybdate tetrahydrate (30 mg) was added to a methanol(6 ml) solution of(2′S)-5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]-2-[2′-(hydroxymethyl)pyrrolidin-1′-yl]pyridine(39 mg, 0.08 mmol), followed by the further addition of 30% aqueoushydrogen peroxide (3 ml). The resulting mixture was stirred for 17hours. The reaction mixture was diluted with ethyl acetate (60 ml). Thediluted mixture was washed with water and brine and concentrated underreduced pressure. The residue thus obtained was purified by silica gelchromatography (hexane:ethyl acetate=1:1) to give the title compound (33mg, 79%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 1.75(1H,m), 2.02(3H,m), 3.3-3.5(1H,m),3.52-3.75(3H,m), 4.2-4.35(1H,m), 6.05(1H,br-s), 6.84(1H,m), 6.96(1H,m),7.36(1H,s), 7.36 and 7.37(2H,d,J=8.8 Hz,rotamer), 7.43(1H,m), 7.53 and7.54(2H,d,J=8.8 Hz,rotamer), 7.89 and 7.90(1H,s,rotamer). FAB-MS:513.0627(Calcd for C₂₃H₂₁Cl₂F₂N₂O₃S: 513.0618).

Example 112t-Butyl[4-[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]morpholin-2-yl]methylcarbamate

A 1,4-dioxane (1.0 ml) solution of the t-butyl2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(60 mg, 0.14 mmol) obtained in Example 54 andt-butyl(morpholin-2-yl)methylcarbamate (200 mg) was stirred at 100° C.for 2 days under a nitrogen atmosphere. After cooling to roomtemperature, the reaction mixture was diluted with ethyl acetate (50ml). The diluted mixture was washed with water and brine, dried andconcentrated under reduced pressure. The residue thus obtained waspurified by silica gel chromatography (hexane:ether=5:1) to give thetitle compound (45 mg, 52%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 1.46(9H,s), 2.72(1H,m), 3.00(1H,m), 3.22(1H,m),3.44(1H,m), 3.6-3.75(2H,m), 3.9-4.1(3H,m), 4.95(1H,br), 5.99 and6.00(1H,s,rotamer), 6.96 and 6.97(1H,s,rotamer), 6.9-7.1(3H,m),7.24(4H,s), 8.11(1H,s).

MSm/z: 596(M⁺+H).

Example 113t-Butyl[4-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]morpholin-2-yl]methylcarbamate

Hexaammonium heptamolybdate tetrahydrate (30 mg) was added to a methanol(6 ml) solution oft-butyl[4-[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]morpholin-2-yl]methylcarbamate(44 mg, 0.074 mmol), followed by the further addition of 30% aqueoushydrogen peroxide (3 ml). The resulting mixture was stirred for 17hours. After the reaction mixture was diluted with ethyl acetate (60ml), the diluted mixture was washed with water and brine, andconcentrated under reduced pressure. The residue thus obtained waspurified by silica gel chromatography (hexane:ethyl acetate=3:1) to givethe title compound (31 mg, 67%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 1.40(9H,s), 2.69(1H,m), 3.02(1H,m), 3.18(1H,m),3.41(1H,br), 3.6-3.75(2H,m), 3.92(1H,m), 4.02(1H,m), 4.13(1H,m),4.91(1H,br), 6.07(1H,s), 6.85(1H,m), 6.99(1H,m), 7.37(2H,d,J=8.4 Hz),7.35-7.45(2H,m), 7.53(2H,d,J=8.4 Hz), 8.17(1H,s).

FAB-MS: 628.1255 (Calcd for C₂₈H₃₀Cl₂F₂N₃O₅S: 628.1251).

Example 1142-Aminomethyl-4-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]morpholine

In methylene chloride (1.5 ml) was dissolved t-butyl[4-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]morpholin-2-yl]methylcarbamate(30 mg, 0.05 mmol). To the resulting solution were added anisole (30 μl)and trifluoroacetic acid (150 μl) at room temperature. The resultingmixture was stirred for 1 hour. The residue obtained by concentratingthe reaction mixture under reduced pressure was purified by silica gelchromatography (3% methanol/chloroform→3% methanol, 3%t-butylamine/chloroform) to give the title compound (17 mg, 67%) as anoil.

¹H-NMR(400 MHz,CDCl₃)δ: 2.77(1H,m), 2.9-3.3(2H,m), 3.5-3.85(3H,m),3.97(1H,m), 4.04-4.25(2H,m), 6.12(1H,s), 6.90(1H,m), 7.02(1H,m),7.42(2H,d,J=8.4 Hz), 7.4-7.55(2H,m), 7.58(2H,d, J=8.4 Hz), 8.05(1H,s).

FAB-MS: 528.0695 (Calcd for C₂₃H₂₂Cl₂F₂N₃O₃S: 528.0727).

Example 1155-Chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]-2-(4′-hydroxypiperidin-1′-yl)pyridine

A 1,4-dioxane (1.0 ml) solution of the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(60 mg, 0.14 mmol) obtained in Example 54 and 4-hydroxypiperidine (200mg) was stirred at 100° C. for 1 day under a nitrogen atmosphere. Aftercooling to room temperature, the reaction mixture was diluted withdiethyl ether (50 ml). The diluted mixture was washed with water andbrine, dried and then concentrated under reduced pressure. The residuethus obtained was purified by silica gel chromatography (hexane:ethylacetate=3:1) to give the title compound (30 mg, 43%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 1.62(0.2H,m), 2.05(2H,m), 3.30(2H,m),3.98(3H,m), 5.97(1H,s), 6.96-7.12(3H,m), 7.23(4H,m), 7.26(1H,s),8.10(1H,s).

MSm/z: 481(M⁺+H).

Example 1165-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]-2-(4′-hydroxypiperidin-1′-yl)pyridine

Hexaammonium heptamolybdate tetrahydrate (30 mg) was added to a methanol(6 ml) solution of5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]-2-(4′-hydroxypiperidin-1′-yl)pyridine(29 mg, 0.06 mmol), followed by the further addition of 30% aqueoushydrogen peroxide (3 ml). The resulting mixture was stirred for 17hours. The reaction mixture was diluted with ethyl acetate (60 ml). Thediluted mixture was washed with water and brine, and concentrated underreduced pressure. The residue thus obtained was purified by silica gelchromatography (hexane:ethyl acetate=2:1), followed by crystallizationfrom ether to give the title compound (17 mg, 55%) as a solid.

¹H-NMR(400 MHz,CDCl₃)δ: 1.64(2H,m), 2.02(2H,m), 3.33(2H,m), 3.98(1H,m),4.08(2H,m), 6.11(1H,s), 6.92(1H,m), 7.02(1H,m), 7.42(2H,d,J=8.8 Hz),7.45(1H,m), 7.53(1H,s), 7.58(2H,d,J=8.8 Hz), 8.05(1H,s).

mp: 146 to 148° C.

FAB-MS: 513.0588 (Calcd for C₂₃H₂₁Cl₂F₂N₂O₃S: 513.0618).

Example 1173,6-Dichloro-2-[(4-chlorophenylsulfonyl)(pyridin-4-yl)methyl]pyridine

To a methylene chloride (10 ml) solution of the(3,6-dichloropyridin-2-yl)(pyridin-4-yl)methanol (161 mg, 0.631 mmol)obtained in Referential Example 25 were added triethylamine (208 μl,1.89 mmol) and thionyl chloride (138 μl, 1.89 mmol). The resultingmixture was stirred at room temperature for 4 hours, followed byconcentration under reduced pressure. To the residue thus obtained wasadded ethyl acetate. The resulting mixture was washed sequentially witha saturated aqueous solution of sodium bicarbonate and brine, dried overanhydrous sodium sulfate and filtered. The filtrate was concentratedunder reduced pressure. The residue thus obtained was dissolved inacetonitrile (10 ml). To the resulting solution were added4-chlorobenzenethiol (137 mg, 0.947 mmol) and potassium carbonate (131mg, 0.947 mmol). Under a nitrogen atmosphere, the resulting mixture wasstirred at room temperature for 2 days and then, stirred at 60° C. for 4hours. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. To the residue was added ethylacetate. The resulting mixture was washed sequentially with water andbrine, dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated under reduced pressure. The residue thus obtained wassubjected to flash chromatography. The fraction obtained from the 40%ethyl acetate/hexane eluate was concentrated under reduced pressure. Theresidue thus obtained was dissolved in methanol (10 ml). To theresulting solution were added 30% aqueous hydrogen peroxide (3 ml) andhexaammonium heptamolybdate tetrahydrate (73 mg). After the resultingmixture was stirred at room temperature for 5 hours, methanol wasdistilled off under reduced pressure. To the solution thus obtained wasadded a saturated aqueous solution of sodium bicarbonate, followed byextraction with methylene chloride. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentratedunder reduced pressure. The residue thus obtained was subjected to flashchromatography. The fraction obtained from the methanol:methylenechloride=1:80 eluate was concentrated under reduced pressure to give thetitle compound (49 mg, 0.118 mmol, 19%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 6.08(1H,s), 7.31(1H,d,J=8.3 Hz), 7.41(2H,d,J=8.8Hz), 7.45(2H,d,J=6.0 Hz), 7.51(2H,d,J=8.8 Hz), 7.69(1H,d,J=8.3 Hz),8.58(2H,d,J=6.0 Hz).

MS(m/z): 413,415(M⁺+H).

Example 1182-[1-(4-Chlorophenylsulfonyl)-1-(2,5-difluorophenyl)ethyl]-5-methylpyridine

An N,N-dimethylformamide (5 ml) solution of the2-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]-5-methylpyridine(52 mg, 0.132 mmol) obtained in Example 15 was added dropwise to anN,N-dimethylformamide (5 ml) suspension of sodium hydride (60% in oil)(30 mg, 0.75 mmol) under ice cooling. After the reaction mixture wasstirred for 15 minutes under ice cooling, methyl iodide (12 μl, 0.198mmol) was added thereto. After stirring at room temperature for 1 hour,water was added to the reaction mixture under ice cooling. The resultingmixture was concentrated under reduced pressure. To the residue wasadded water and the resulting mixture was extracted with ethyl acetate.The organic layer was washed with brine, dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated under reducedpressure. The residue thus obtained was subjected to silica gel columnchromatography. The fraction obtained from the hexane:ethyl acetate=8:1eluate was concentrated under reduced pressure. The residue thusobtained was solidified with hexane and collected by filtration to givethe title compound (50 mg, 0.122 mmol, 93%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 2.14(3H,s), 2.33(3H,s), 6.80-7.10(2H,m),7.23-7.34(4H,m), 7.39-7.51(2H,m), 7.88-8.00(1H,m), 8.15(1H,s).

MS (m/z): 408 (M⁺+H).

Example 1193,6-Dichloro-2-[(6-chloropyridin-3-ylthio)(pyridin-4-yl)methyl]pyridine

To an ethanol (7 ml) solution of the O-ethyl S-(6-chloro-3-pyridyl)dithiocarbonate (164 mg, 0.70 mmol) obtained in Referential Example 26was added a 1N aqueous sodium hydroxide solution (7 ml). The resultingmixture was stirred at 80° C. for 3 hours. After the reaction mixturewas cooled to room temperature, 1N hydrochloric acid was added thereto.The resulting mixture was extracted with dichloromethane. The organiclayer was dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated under reduced pressure to give 6-chloro-3-pyridinethiolas a yellow solid.

To a dichloromethane (3 ml) solution of the(3,6-dichloropyridin-2-yl)(pyridin-4-yl)methanol (153 mg, 0.60 mmol)obtained in Referential Example 25 were added triethylamine (0.167 ml,1.20 mmol) and methanesulfonyl chloride (0.070 ml, 0.90 mmol)sequentially at 0° C. The resulting mixture was stirred at roomtemperature for 2 hours. After the reaction mixture was washed with asaturated aqueous solution of sodium bicarbonate, the organic layer wasdried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure. To an N,N-dimethylformamide (3 ml)solution of the residue thus obtained were added anN,N-dimethylformamide (2 ml) solution of 6-chloro-3-pyridinethiol andthen, potassium carbonate (100 mg, 0.72 mmol). The resulting mixture wasstirred at room temperature for 18 hours. To the reaction mixture wasadded ethyl acetate. The resulting mixture was washed with a saturatedaqueous solution of sodium bicarbonate. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentratedunder reduced pressure. The residue thus obtained was subjected to flashsilica gel chromatography. The fraction obtained from the hexane:ethylacetate=7:3 eluate was concentrated under reduced pressure to give thetitle compound (83 mg, 0.22 mmol, 36%) as a yellow oil.

¹H-NMR(400 MHz,CDCl₃)δ: 5.69(1H,s), 7.20(1H,d,J=8.3 Hz), 7.24(1H,d,J=8.3Hz), 7.35(2H,d,J=6.1 Hz), 7.52(1H,dd,J=8.3,2.4 Hz), 7.62(1H,d,J=8.3 Hz),8.32(1H,d,J=2.4 Hz), 8.55(2H,d,J=6.1 Hz).

MSm/z: 382(M⁺+H).

Example 1203,6-Dichloro-2-[(6-chloropyridin-3-ylsulfonyl)(pyridin-4-yl)methyl]pyridine(Compound A) and3,6-dichloro-2-[(6-chloropyridin-3-ylsulfinyl)(pyridin-4-yl)methyl]pyridine(Compound B (Isomer A) and Compound B (Isomer B))

To a methanol (4 ml) solution of3,6-dichloro-2-[(6-chloropyridin-3-ylthio)(pyridin-4-yl)methyl]pyridine(82 mg, 0.24 mmol) were added 31% aqueous hydrogen peroxide (2 ml) andhexaammonium heptamolybdate tetrahydrate (30 mg). The resulting mixturewas stirred at room temperature for 2 hours. To the reaction mixture wasadded ethyl acetate. The resulting mixture was washed with a saturatedaqueous solution of sodium bicarbonate. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentratedunder reduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=3:2 eluate was concentrated under reduced pressureto give the title Compound A (41 mg, 0.098 mmol, 46%), while thefraction obtained from the hexane:ethyl acetate=1:1 eluate wasconcentrated under reduced pressure to give the title Compound B (IsomerA) (low polarity) (8 mg, 9%) and the title Compound B (Isomer B) (highpolarity) (8 mg, 9%), each as a white solid.

Compound A

¹H-NMR(400 MHz,CDCl₃)δ: 6.11(1H,s), 7.35(1H,d,J=8.3 Hz), 7.36(2H,d,J=6.1Hz), 7.40(1H,d,J=8.3 Hz), 7.73(1H,d,J=8.3 Hz), 7.78(1H,dd,J=8.3,2.4 Hz),8.48(1H,d,J=2.4 Hz), 8.61(2H,d, J=6.1 Hz).

MSm/z: 414 (M⁺+H).

Compound B (Isomer A)

¹H-NMR(400 MHz,CDCl₃)δ: 5.54(1H,s), 6.99(2H,d,J=6.1 Hz), 7.27(1H,d,J=8.3Hz), 7.37(1H,d,J=8.3 Hz), 7.55(1H,dd,J=8.3,2.2 Hz), 7.73(1H,d,J=8.3 Hz),8.47(1H,d,J=2.2 Hz), 8.51(2H,d,J=6.1 Hz).

MSm/z: 398(M⁺+H).

Compound B (Isomer B)

¹H-NMR(400 MHz,CDCl₃)δ: 5.40(1H,s), 7.26(1H,d,J=8.5 Hz), 7.42(1H,d,J=8.3Hz), 7.53(2H,d,J=6.1 Hz), 7.57(1H,d,J=8.5 Hz), 7.96(1H,dd,J=8.3,2.4 Hz),8.34(1H,d,J=2.4 Hz), 8.68(2H,d,J=6.1 Hz).

MSm/z: 398 (M⁺+H).

Example 1212-[[(3-Chloropyridin-4-yl)(2,5-difluorophenyl)methyl]sulfonyl]pyrimidine

To a dichloromethane (4 ml) solution of the3-chloro-4-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (102 mg, 0.40mmol) obtained in Referential Example 23 were added triethylamine (0.112ml, 0.80 mmol) and methanesulfonyl chloride (0.046 ml, 0.60 mmol)sequentially at 0° C. The resulting mixture was stirred at roomtemperature for 17 hours. The reaction mixture was washed with asaturated aqueous solution of sodium bicarbonate. The organic layer wasdried over anhydrous sodium sulfate and filtered. The filtrate was thenconcentrated under reduced pressure.

To an N,N-dimethylformamide (4 ml) solution of the resulting residuewere added 2-pyrimidinethiol (45 mg, 0.40 mmol) and then, potassiumcarbonate (83 mg, 0.60 mmol). The resulting mixture was stirred at roomtemperature for 23 hours. To the reaction mixture was added ethylacetate. The resulting mixture was washed with water. The organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure. To a dichloromethane (4 ml)solution of the resulting residue was added 3-chloroperbenzoic acid(purity: 65% or greater) (212 mg, 0.80 mmol) at 0° C. The resultingmixture was stirred at room temperature for 3 hours. After the reactionmixture was washed with a 1N aqueous solution of sodium hydroxide, theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure. The residue thusobtained was subjected to flash silica gel chromatography. The fractionobtained from the hexane:ethyl acetate=2:3 eluate was concentrated underreduced pressure to give the title compound (19 mg, 0.049 mmol, 12%) asa colorless foamy substance.

¹H-NMR(400 MHz,CDCl₃)δ: 6.26(1H,s), 6.93-7.13(3H,m), 7.50-7.56(1H,m),8.01-8.08(1H,m), 8.13(1H,d,J=5.1 Hz), 8.48(1H,d,J=2.2 Hz), 8.60(1H,s),8.66(1H,d,J=5.1 Hz).

MSm/z: 382(M⁺+H).

Example 1226-(4-Chlorophenylthio)(2,5-difluorophenyl)methyl-5-fluoronicotinamide

To a dichloromethane (4 ml) solution of the6-(2,5-difluorophenyl)hydroxymethyl-5-fluoronicotinamide (114 mg, 0.40mmol) obtained in Referential Example 31 were added triethylamine (0.113ml, 0.81 mmol) and methanesulfonyl chloride (0.047 ml, 0.61 mmol)sequentially at 0° C. The resulting mixture was stirred at roomtemperature for 2 hours. The reaction mixture was washed with asaturated aqueous solution of sodium bicarbonate. The organic layer wasdried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure.

To an N,N-dimethylformamide (6 ml) solution of the residue thus obtainedwere added 4-chlorobenzenethiol (70 mg, 0.49 mmol) and then, potassiumcarbonate (67 mg, 0.49 mmol). The resulting mixture was stirred at roomtemperature for 15 hours. To the reaction mixture was added ethylacetate. The resulting mixture was washed with a saturated aqueoussolution of sodium bicarbonate. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentratedunder reduced pressure. The residue thus obtained was subjected to flashsilica gel chromatography. The fraction obtained from the hexane:ethylacetate=1:1 eluate was concentrated under reduced pressure to give thetitle compound (120 mg, 0.29 mmol, 73%) as a yellow solid.

¹H-NMR(400 MHz,CDCl₃): 6.14(1H,s), 6.88-6.96(2H,m), 7.21(2H,d,J=8.5 Hz),7.28(2H,d,J=8.5 Hz), 7.58-7.74(1H,m), 7.85(1H,dd,J=9.4,1.6 Hz),8.80(1H,s).

MSm/z: 409(M⁺+H).

Example 1236-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoronicotinamide(Compound A) and6-(4-chlorophenylsulfinyl)(2,5-difluorophenyl)methyl-5-fluoronicotinamide(Compound B)

To a methanol (3 ml) solution of6-(4-chlorophenylthio)(2,5-difluorophenyl)methyl-5-fluoronicotinamide(120 mg, 0.29 mmol) were added 30% aqueous hydrogen peroxide (2 ml) andhexaammonium heptamolybdate tetrahydrate (73 mg). The resulting mixturewas stirred at room temperature for 3 hours. To the reaction mixture wasadded dichloromethane. The resulting mixture was washed with a saturatedaqueous solution of sodium bicarbonate. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentratedunder reduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=1:1 eluate was concentrated under reduced pressureto give the title Compound A (33 mg, 0.075 mmol, 25%) as a white solid.The fraction obtained from the hexane:ethyl acetate=1:3 eluate wasconcentrated under reduced pressure to give the title Compound B (39 mg,0.092 mmol, 31%) as a white solid.

Compound A

¹H-NMR(400 MHz,CDCl₃)δ: 6.37(1H,s), 6.90-6.97(1H,m), 7.01-7.08(1H,m),7.43(2H,d,J=8.5 Hz), 7.58(2H,d,J=8.5 Hz), 7.94(1H,dd,J=9.2,1.8 Hz),8.17-8.22(1H,m), 8.91(1H,s).

mp: 222 to 224° C.

MSm/z: 441(M⁺+H).

Compound B

¹H-NMR(400 MHz,CD₃OD)δ: 5.86(1H,s), 6.94-7.02(1H,m), 7.06-7.14(1H,m),7.44(2H,d,J=8.8 Hz), 7.48(2H,d,J=8.8 Hz), 7.66-7.71(1H,m),8.07(1H,dd,J=9.8,1.7 Hz), 9.09(1H,s).

mp: 171 to 173° C.

Elemental Analysis for C₁₉H₁₂ClF₃N₂O₂S: Calculated: C, 53.72; H, 2.85;Cl, 8.35; F, 13.42; N, 6.59; S, 7.55. Found: C, 53.44; H, 2.96; Cl,8.37; F, 13.34; N, 6.66; S, 7.54.

Example 124[6-(4-Chlorophenylthio)(2,5-difluorophenyl)methyl-5-fluoropyridin-3-yl]methanol

To a dichloromethane (180 ml) solution of the[5-(t-butyldiphenylsilyloxymethyl)-3-fluoropyridin-2-yl](2,5-difluorophenyl)methanol(17.0 g, 33.5 mmol) obtained in Referential Example 29 were addedtriethylamine (7.00 ml, 50.2 mmol) and methanesulfonyl chloride (3.11ml, 40.2 mmol) at room temperature. The resulting mixture was stirredfor 2 hours. The reaction mixture was washed with a saturated aqueoussolution of sodium bicarbonate. The organic layer was then dried overanhydrous sodium sulfate and filtered. The filtrate was concentratedunder reduced pressure.

To an N,N-dimethylformamide (300 ml) solution of the residue thusobtained were added 4-chlorobenzenethiol (5.33 g, 36.8 mmol) andpotassium carbonate (5.55 g, 40.2 mmol) sequentially. The resultingmixture was stirred at room temperature for 18 hours. To the reactionmixture was added ethyl acetate. The resulting mixture was washed with asaturated aqueous solution of sodium bicarbonate. The organic layer wasdried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel chromatography. The fraction obtained fromthe hexane:ethyl acetate=30:1 eluate was concentrated under reducedpressure.

To a tetrahydrofuran (200 ml) solution of the residue thus obtained wasadded a tetrahydrofuran solution (42.3 ml, 42.3 mmol) oftetrabutylammonium fluoride. The resulting mixture was stirred at roomtemperature for 4 hours. The reaction mixture was concentrated underreduced pressure and the residue thus obtained was dissolved in ethylacetate. The resulting solution was washed with a saturated aqueoussolution of sodium bicarbonate. The organic layer was dried overanhydrous sodium sulfate, and filtered. The filtrate was thenconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel chromatography. The fraction obtained fromthe hexane:ethyl acetate=3:1 eluate was concentrated under reducedpressure to give the title compound (9.80 g, 24.8 mmol, 74%) as acolorless oil.

¹H-NMR(400 MHz,CDCl₃)δ: 4.76(2H,s), 6.13(1H,s), 6.84-6.96(2H,m),7.20(2H,d,J=8.7 Hz), 7.27(2H,d,J=8.7 Hz), 7.43(1H,d,J=9.8 Hz),7.57-7.64(1H,m), 8.43(1H,s).

Example 125[6-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoropyridin-3-yl]methanol

To a methanol (200 ml) solution of[6-(4-chlorophenylthio)(2,5-difluorophenyl)methyl-5-fluoropyridin-3-yl]methanol(9.80 g, 24.8 mmol) were added 30% aqueous hydrogen peroxide (14.0 ml)and hexaammonium heptamolybdate tetrahydrate (612 mg). The resultingmixture was stirred at room temperature for 18 hours. To the reactionmixture was added 30% aqueous hydrogen peroxide (14.0 ml). The resultingmixture was stirred at room temperature for 3 days. To the reactionmixture was added 30% aqueous hydrogen peroxide (14.0 ml) further. Theresulting mixture was stirred at 50° C. for 5 hours. To the reactionmixture was added water and the solid thus precipitated was collected byfiltration. The resulting solid was washed with water and dried underreduced pressure. The solid was dissolved in ethyl acetate. Theresulting solution was washed with a saturated aqueous solution ofsodium bicarbonate. The organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated under reducedpressure. The residue was recrystallized from ethanol to give the titlecompound (6.41 g, 15.0 mmol, 61%) as a white solid. After the baseliquid was concentrated under reduced pressure, the residue wasrecrystallized from ethanol to give the title compound (2.14 g, 5.00mmol, 20%) as a white solid. After the base liquid was concentratedunder reduced pressure further, the residue was washed with diethylether and collected by filtration to give the title compound (780 mg,1.82 mmol, 7%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 1.90(1H,t,J=5.6 Hz), 4.80(2H,d,J=5.6 Hz),6.32(1H,s), 6.89-6.97(1H,m), 6.99-7.06(1H,m), 7.41(2H,d,J=8.8 Hz),7.49(1H,d,J=9.8 Hz), 7.57(2H,d,J=8.8 Hz), 8.18-8.24(1H,m), 8.52(1H,s).

mp: 181 to 183° C.

MSm/z: 428(M⁺+H).

Example 126[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropyridin-3-yl]carbaldehyde

To a dichloromethane (100 ml) solution of[6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoropyridin-3-yl]methanol(8.46 g, 19.8 mmol), triethylamine (13.8 ml, 98.9 mmol) anddimethylsulfoxide (7.02 ml, 98.9 ml) was added sulfur trioxide pyridinecomplex (9.44 g, 59.3 mmol) at room temperature. The resulting mixturewas stirred for 16 hours. After the reaction mixture was washed withbrine, the organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure. Theresidue was subjected to flash silica gel chromatography. The fractionobtained from the dichloromethane eluate was concentrated under reducedpressure. The residue thus obtained was washed with diethyl ether andcollected by filtration to give the title compound (6.33 g, 14.9 mmol,75%) as a yellow solid.

¹H-NMR(400 MHz,CDCl₃)δ: 6.40(1H,s), 6.91-6.98(1H,m), 7.02-7.09(1H,m),7.43(2H,d,J=8.6 Hz), 7.59(2H,d,J=8.6 Hz), 7.89(1H,dd,J=8.6,1.7 Hz),8.17-8.23(1H,m), 9.02(1H,s), 10.15 (1H, d, J=2.2 Hz).

Example 1276-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoronicotinicacid

To a formic acid (30 ml) solution of[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropyridin-3-yl]carbaldehyde(1.28 g, 3.00 mmol) was added 30% aqueous hydrogen peroxide (1.02 ml,9.00 ml) at room temperature. The resulting mixture was stirred at roomtemperature for 1 hour. The reaction mixture was stirred further at 50°C. for 1 hour. After cooling to room temperature, water was addedthereto. The solid thus precipitated was collected by filtration, washedwith water, and dried under reduced pressure. The solid thus obtainedwas dissolved in ethyl acetate. The resulting solution was washed with asaturated aqueous solution of ammonium chloride. The organic layer wasdried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure. The residue was washed with ethanoland collected by filtration to give the title compound (1.19 g, 2.69mmol, 89%) as a white solid.

¹H-NMR(400 MHz,DMSO-d₆)δ: 6.37(1H,s), 7.27-7.42(2H,m), 7.64(2H,d,J=8.8Hz), 7.67(2H,d,J=8.8 Hz), 8.01-8.07(1H,m), 8.17(1H,dd,J=9.6,1.7 Hz),9.04(1H,s).

mp: 249 to 251° C.

Elemental Analysis for C₁₉H₁₁ClF₃NO₄S: Calculated: C, 51.65; H, 2.51;Cl, 8.02; F, 12.90; N, 3.17; S, 7.26. Found: C, 51.70; H, 2.73; Cl,7.96; F, 12.81; N, 3.36; S, 7.39.

Example 1286-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoro-N-thiazol-2-ylnicotinamide

To a dichloromethane (2 ml) solution were added6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoronicotinicacid (100 mg, 0.23 mmol) were added thiazol-2-ylamine (25 mg, 0.25mmol), benzotriazol-1-ol (34 mg, 0.25 mmol), 4-methylmorpholine (0.027ml, 0.25 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (48 mg, 0.25 mmol) at room temperature. The resultingmixture was stirred at room temperature for 14 hours. To the reactionmixture was added ethyl acetate. The resulting mixture was washed with asaturated aqueous solution of sodium bicarbonate. The organic layer wasdried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel chromatography. The fraction obtained fromthe hexane:ethyl acetate=3:1 eluate was concentrated under reducedpressure. The residue was washed with ethanol and collected byfiltration to give the title compound (72 mg, 0.14 mmol, 60%) as a whitesolid.

¹H-NMR(400 MHz,DMSO-d₆)δ: 6.38(1H,s), 7.24-7.42(2H,m), 7.60(1H,d,J=3.7Hz), 7.65(2H,d,J=9.1 Hz), 7.68(2H,d,J=9.1 Hz), 8.03-8.10(1H,m),8.38(1H,d,J=9.6 Hz), 9.17(1H,s), 13.00(1H,s).

mp: 243 to 245° C.

Elemental Analysis for Calcd for C₂₂H₁₃ClF₃N₃O₃S₂: Calculated: C, 50.43;H, 2.50; Cl, 6.77; F, 10.88; N, 8.02; S, 12.24. Found: C, 50.34; H,2.48; Cl, 6.93; F, 10.82; N, 8.11; S, 12.29.

Example 1296-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoro-N-isoxazol-3-ylnicotinamide

In a similar manner to Example 128, the title compound (43 mg, 0.085mmol, 37%) as a white solid by using the6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoronicotinicacid (100 mg, 0.23 mmol) obtained in Example 127 and isoxazol-3-ylamine(0.018 ml, 0.25 mmol).

¹H-NMR(400 MHz,CDCl₃)δ: 6.41(1H,s), 6.92-7.00(1H,m), 7.03-7.11(1H,m),7.25(1H,d,J=1.7 Hz), 7.44(2H,d,J=8.6 Hz), 7.60(2H,d,J=8.6 Hz),8.05(1H,dd,J=9.1,2.0 Hz), 8.20-8.26(1H,m), 8.40(1H,d,J=1.7 Hz),9.14(1H,d,J=1.5 Hz), 10.25(1H,s).

mp: 200 to 202° C.

Elemental Analysis for Calcd for C₂₂H₁₃ClF₃N₃O₄S: Calculated: C, 52.03;H, 2.58; Cl, 6.98; F, 11.22; N, 8.27; S, 6.31. Found: C, 51.84; H, 2.55;Cl, 7.36; F, 11.19; N, 8.36; S, 6.46.

Example 1306-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoro-N-pyridin-2-ylmethylnicotinamide

In a similar manner to Example 128, the title compound (86 mg, 0.16mmol, 72%) as a colorless amorphous substance by using the6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoronicotinicacid (100 mg, 0.23 mmol) obtained in Example 127 andpyridin-2-ylmethylamine (0.026 ml, 0.25 mmol).

¹H-NMR(400 MHz,CDCl₃)δ: 4.77(2H,d,J=4.4 Hz), 6.37(1H,s),6.91-7.09(2H,m), 7.25-7.34(2H,m), 7.43(2H,d,J=8.8 Hz), 7.58(2H,d,J=8.8Hz), 7.72(1H,td,J=7.6,1.7 Hz), 7.94(1H,s), 7.96(1H,dd,J=9.3,2.0 Hz),8.19-8.25(1H,m), 8.59(1H,d,J=4.4 Hz), 9.03(1H,s).

Elemental Analysis for Calcd for C₂₅H₁₇ClF₃N₃O₃S: Calculated: C, 56.45;H, 3.22; Cl, 6.66; F, 10.71; N, 7.90; S, 6.03. Found: C, 56.32; H, 3.30;Cl, 6.63; F, 10.61; N, 7.88; S, 6.14.

Example 131 Methyl(E)-3-[6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoropyridin-3-yl]acrylate

To a tetrahydrofuran (15 ml) solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropyridin-3-yl]carbaldehyde(1.70 g, 4.00 mmol) obtained in Example 126 was addedmethyl(triphenylphosphoranylidene)acetate (1.47 g, 4.40 mmol) at roomtemperature. The resulting mixture was stirred at room temperature for18 hours. The reaction mixture was concentrated under reduced pressure.The residue thus obtained was subjected to flash silica gelchromatography. The fraction obtained from the dichloromethane eluatewas concentrated under reduced pressure. The residue thus obtained waswashed with a mixed solvent of ethanol and hexane and then, collected byfiltration to give the title compound (1.60 g, 3.31 mmol, 83%) as awhite solid.

¹H-NMR(400 MHz,CDCl₃)δ: 3.84(3H,s), 6.33(1H,s), 6.53(1H,d,J=16.7 Hz),6.89-6.97(1H,m), 6.99-7.08(1H,m), 7.42(2H,d,J=8.3 Hz),7.55(1H,d,J=9.6,1.5 Hz), 7.58(2H,d,J=8.3 Hz), 7.65(1H,d,J=16.7 Hz),8.18-8.24(1H,m), 8.67(1H,s).

MSm/z: 482(M⁺+H).

Example 132 Methyl3-[6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoropyridin-3-yl]propionate

A Raney nickel suspension (“R-100”, product of Nikko Rica Corporation)(1 ml) was washed sequentially with water and ethanol to give an ethanol(10 ml) suspension. The resulting suspension was added to an ethanol (40ml) solution of methyl3-[6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoropyridin-3-yl]acrylate(1.38 g, 2.86 mmol). Under a hydrogen atmosphere, the resulting mixturewas stirred a t room temperature for 1 hour. The reaction mixture wasfiltered through Celite and the filtrate was concentrated under reducedpressure. The residue thus obtained was dissolved in dichloromethane.The resulting solution was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure to givethe title compound 1.37 g, 2.83 mmol, 99%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 2.66(2H,t,J=7.4 Hz), 3.00(2H,t,J=7.4 Hz),3.69(3H,s), 6.29(1H,s), 6.88-6.96(1H,m), 6.98-7.06(1H,m),7.29(1H,dd,J=10.1,1.5 Hz), 7.40(2H,d,J=8.3 Hz), 7.56(2H,d,J=8.3 Hz),8.20-8.26(1H,m), 8.42(1H,s).

MSm/z: 484(M⁺+H).

Example 1333-[6-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoropyridin-3-yl]propionicacid

To an ethanol (8 ml) solution of methyl3-[6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoropyridin-3-yl]propionate(387 mg, 0.80 mmol) was added a 1N aqueous sodium hydroxide solution (4ml). The resulting mixture was stirred at room temperature for 3 hours.The reaction mixture was acidified with 1N hydrochloric acid, followedby extraction with dichloromethane. The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentratedunder reduced pressure. The residue thus obtained was washed with amixed solvent of diethyl ether and hexane and then collected byfiltration to give the title compound (349 mg, 0.74 mmol, 93%) as awhite solid.

¹H-NMR(400 MHz,CDCl₃)δ: 2.73(2H,t,J=7.4 Hz), 3.01(2H,t,J=7.4 Hz),6.29(1H,s), 6.89-6.96(1H,m), 6.99-7.06(1H,m), 7.30(1H,dd,J=9.8,1.7 Hz),7.40(2H,d,J=8.6 Hz), 7.56(2H,d,J=8.6 Hz), 8.19-8.26(1H,m), 8.44(1H,s).

mp: 174 to 176° C.

MSm/z: 470(M⁺+H).

Elemental Analysis for C₂₁H₁₅ClF₃NO₄S: Calculated: C, 53.68; H, 3.22;Cl, 7.55; F, 12.13; N, 2.98; S, 6.82. Found: C, 53.68; H, 3.35; Cl,7.42; F, 12.09; N, 3.16; S, 6.92.

Example 1343-[6-(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoropyridin-3-yl]-1-(4-methylpiperazin-1-yl)propan-1-onehydrochloride

To a dichloromethane (3 ml) solution of3-[6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoropyridin-3-yl]propionicacid (100 mg, 0.21 mmol) were added 1-methylpiperazine (0.026 ml, 0.23mmol), benzotriazol-1-ol (32 mg, 0.23 mmol), 4-methylmorpholine (0.026ml, 0.23 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (45 mg, 0.23 mmol) at room temperature. The resultingmixture was stirred at room temperature for 16 hours. After the reactionmixture was washed with a saturated aqueous solution of sodiumbicarbonate, the organic layer was dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated under reduced pressure. Theresidue thus obtained was subjected to flash silica gel chromatography.The fraction obtained from the dichloromethane:methanol=19:1 eluate wasconcentrated under reduced pressure. The residue was dissolved inethanol (3 ml), followed by the addition of 1N hydrochloric acid (0.224ml). After stirring at room temperature for 30 minutes, the reactionmixture was concentrated under reduced pressure. The residue thusobtained was washed with ethanol and collected by filtration to give thetitle compound (111 mg, 0.19 mmol, 89%) as a white solid.

¹H-NMR(400 MHz,DMSO-d₆)δ: 2.40-3.08(6H,m), 2.75(3H,s), 2.90(2H,t,J=7.1Hz), 3.19-3.50(2H,m), 3.92-4.17(1H,m), 4.29-4.52(1H,m), 6.23(1H,s),7.24-7.39(2H,m), 7.61(2H,d,J=8.8 Hz), 7.66 (2H,d,J=8.8 Hz),7.75(1H,dd,J=10.8,1.5 Hz), 8.10-8.16(1H,m), 8.53(1H,s), 10.70(1H,s).

mp: 243 to 245° C.

Elemental Analysis for C₂₆H₂₅ClF₃N₃O₃S—HCl: Calculated: C, 53.07; H,4.45; Cl, 12.05; F, 9.69; N, 7.14; S, 5.45. Found: C, 52.81; H, 4.51;Cl, 11.74; F, 9.48; N, 7.09; S, 5.50.

Example 135(E)-3-[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]acrylicacid

A tetrahydrofuran solution (5 ml) of the methyl(E)-3-[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]acrylate(460 mg, 0.991 mmol) obtained in Example 44 was added a 1N sodiumhydroxide solution (3.0 ml). The resulting mixture was stirred at roomtemperature for 4 hours. The reaction mixture was acidified with 1Nhydrochloric acid, followed by extraction with ethyl acetate. Theextract was washed with water and brine, dried over magnesium sulfateand concentrated. The crude title compound was obtained at astoichiometric ratio. A portion of the resulting solid wasrecrystallized from ethyl acetate-hexane to give the title compound(29.4 mg, 0.0653 mmol) as a colorless solid.

¹H-NMR(400 MHz,CDCl₃)δ: 5.96(1H,s), 6.52(1H,d,J=16.1 Hz), 6.94(1H,td,J=9.0,4.6 Hz), 6.99-7.06(1H,m), 7.41(2H,d,J=8.6 Hz),7.56(2H,d,J=8.6 Hz), 7.64(1H,d,J=16.1 Hz), 7.64(1H,d,J=8.1 Hz),7.88(1H,dd,J=8.1,2.2 Hz), 8.01(1H,ddd,J=9.0,5.6,3.4 Hz), 8.72(1H,d,J=2.2Hz).

mp: 236 to 238° C.

Elemental Analysis for C₂₁H₁₄ClF₂NO₄S: Calculated: C, 56.07; H, 3.14;Cl, 7.88; F, 8.45; N, 3.11; S, 7.13. Found: C, 55.98; H, 3.21; Cl, 7.90;F, 8.45; N, 3.21; S, 7.12.

Example 136(E)-3-[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]acrylamide

In dichloromethane (6 ml) was dissolved(E)-3-[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]acrylicacid (370 mg, 0.822 mmol). To the resulting solution were added thionylchloride (2.00 ml) and N,N-dimethylformamide (one drop). The resultingmixture was stirred at room temperature for 4 hours. The reactionmixture was concentrated to dryness. The residue thus obtained wasdissolved in dichloromethane (6 ml), followed by the addition of aqueousconcentrated ammonia (2.00 ml). After stirring at room temperature for 2hours, the reaction mixture was diluted with dichloromethane. Thediluted mixture was washed with water, 0.1N hydrochloric acid and brine,dried over magnesium sulfate, and concentrated. The solid thus obtainedwas recrystallized from ethanol to give the title compound (250 mg,0.558 mmol, 68%) as a white solid.

¹H-NMR(400 MHz,CDCl₃/DMSO-d₆)δ: 5.79(1H,brs), 5.95(1H,s), 6.42(1H,brs),6.63(1H,d,J=15.9 Hz), 6.94(1H,td,J=9.0,4.4 Hz), 7.00-7.07(1H,m),7.41(2H,d,J=8.5 Hz), 7.56(2H,d,J=8.5 Hz), 7.62(1H,d,J=15.9 Hz),7.64(1H,d,J=8.1 Hz), 7.85(1H,dd,J=8.1,2.2 Hz), 8.02(1H,ddd,J=9.0,5.4,3.2Hz), 8.74(1H,d,J=2.2 Hz).

mp: 219 to 220° C.

Elemental Analysis for C₂₁H₁₅ClF₂N₂O₃S: Calculated: C, 56.19; H, 3.37;Cl, 7.90; F, 8.46; N, 6.24; S, 7.14. Found: C, 55.98; H, 3.34; Cl, 8.03;F, 8.45; N, 6.39; S, 7.23.

Example 137 EthylN-[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]nicotinoyl]glycine

To a dichloromethane (5 ml) solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (100 mg, 0.236 mmol) obtained in Example 50 were addedtriethylamine (80 μl, 0.566 mmol), 4-dimethylaminopyridine (14 mg, 0.118mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54mg, 0.283 mmol) and ethyl glycine hydrochloride (40 mg, 0.283 mmol). Theresulting mixture was stirred at room temperature for 7 hours. Thereaction mixture was diluted with dichloromethane. The diluted mixturewas washed sequentially with water, a saturated aqueous solution ofsodium bicarbonate and brine. The organic layer thus obtained was driedover magnesium sulfate, and concentrated under reduced pressure. Theresidue thus obtained was subjected to flash silica gel columnchromatography. The fraction obtained from the hexane:ethyl acetate=2:1eluate was concentrated under reduced pressure to give the titlecompound (95 mg, 0.187 mmol, 79%) as a colorless amorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 1.33(3H,t,J=7.1 Hz), 4.25(2H,d,J=5.1 Hz),4.28(2H,q,J=7.1 Hz), 6.00(1H,s), 6.99(1H,brs), 6.91-6.97(1H,m),7.00-7.06(1H,m), 7.42(2H,d,J=8.5 Hz), 7.56(2H,d,J=8.5 Hz),7.73(1H,d,J=8.3 Hz), 7.96-8.00(1H,m), 8.18(1H,dd,J=8.3,2.2 Hz), 9.01(1H,d,J=2.2 Hz).

MSm/z: 509(M⁺+H).

Example 138t-Butyl[2-[[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridine-3-carbonyl]amino]ethyl]carbamate

To a dichloromethane (5 ml) solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (100 mg, 0.236 mmol) obtained in Example 50 were addedtriethylamine (40 μl, 0.283 mmol), 4-dimethylaminopyridine (14 mg, 0.118mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54mg, 0.283 mmol) and t-butyl N-(2-aminoethyl)carbamate (45 μl, 0.283mmol). The resulting mixture was stirred at room temperature for 6hours. The reaction mixture was diluted with dichloromethane. Thediluted mixture was washed sequentially with water, a saturated aqueoussolution of sodium bicarbonate and brine. The resulting organic layerwas dried over magnesium sulfate, and concentrated under reducedpressure. The residue thus obtained was subjected to flash silica gelcolumn chromatography. The fraction obtained from the hexane:ethylacetate=1:1 eluate was concentrated under reduced pressure to give thetitle compound (57 mg, 0.101 mmol, 43%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 1.44(9H,s), 3.37-3.43(2H,m), 3.55-3.59(2H,m),4.97(1H,brs), 6.00(1H,s), 6.92-7.05(2H,m), 7.40(2H,d,J=8.6 Hz),7.55(2H,d,J=8.6 Hz), 7.60(1H,brs), 7.70(1H,d,J=8.3 Hz), 7.92-7.97(1H,m),8.17(1H,dd,J=8.3,2.4 Hz), 9.03(1H,d,J=2.4 Hz).

MSm/z: 566(M⁺+H).

Example 139N-(2-Aminoethyl)-6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]nicotinamide

To an ethanol (2 ml) solution oft-butyl[2-[[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridine-3-carbonyl]amino]ethyl]carbamate(50 mg, 0.0880 mmol) was added concentrated hydrochloric acid (2 ml).The resulting mixture was stirred at room temperature for 20 minutes.The reaction mixture was concentrated under reduced pressure. The solidthus obtained was washed with diethyl ether to give the title compound(44 mg, 0.0880 mmol, quant.) as 1.5 hydrochloride (white powder).

¹H-NMR(400 MHz,CD₃OD)δ: 3.19(2H,t,J=5.9 Hz), 3.69(2H,d,J=5.9 Hz),6.27(1H,s), 7.03-7.09(1H,m), 7.12-7.18(1H,m), 7.54(2H,d,J=8.6 Hz),7.66(2H,d,J=8.6 Hz), 7.83(1H,d,J=8.3 Hz), 8.06-8.10(1H,m),8.27(1H,dd,J=8.3,2.4 Hz), 9.08(1H,d,J=2.4 Hz).

mp: >250° C. (decomp.).

Elemental Analysis for C₂₁H₁₈ClF₂N₃O₃S.1.5H₂O.1.5HCl: Calculated: C,46.06; H, 4.14; Cl, 16.18; F, 6.94; N, 7.67; S, 5.86. Found: C, 46.39;H, 3.93; Cl, 16.58; F, 6.84; N, 7.74; S, 5.94.

Example 1406-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-N-(2-hydroxyethyl)nicotinamide

A dichloromethane (5 ml) solution of the[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylicacid (100 mg, 0.236 mmol) obtained in Example 50 were addedtriethylamine (80 μl, 0.566 mmol), 4-dimethylaminopyridine (15 mg, 0.118mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54mg, 0.283 mmol) and ethanolamine hydrochloride (28 mg, 0.283 mmol). Theresulting mixture was stirred at room temperature for 17.5 hours. Thereaction mixture was diluted with dichloromethane. The diluted mixturewas washed sequentially with water, a saturated aqueous solution ofsodium bicarbonate and brine. The organic layer thus obtained was driedover magnesium sulfate and concentrated under reduced pressure. Theresidue thus obtained was subjected to flash silica gel columnchromatography. The fraction obtained from thedichloromethane:methanol=30:1 eluate was concentrated under reducedpressure to give the title compound (69 mg, 0.148 mmol, 63%) as a whitepowder.

¹H-NMR(400 MHz,CDCl₃)δ: 2.38(1H,t,J=4.9 Hz), 3.65(2H,td,J=5.4,4.9 Hz),3.85(2H,q,J=4.6 Hz), 5.99(1H,s), 6.77(1H,brs), 6.90-6.96(1H,m),7.00-7.06(1H,m), 7.42(2H,d,J=8.6 Hz), 7.56(2H,d,J=8.6 Hz),7.70(1H,d,J=8.1 Hz), 7.97-8.01(1H,m), 8.15(1H,dd,J=8.1,2.2 Hz),8.99(1H,d,J=2.2 Hz)H,m),

mp: 179 to 181° C.

Elemental Analysis for C₂₁H₁₇ClF₂N₂O₄S: Calculated: C, 54.02; H, 3.67;Cl, 7.59; F, 8.14; N, 6.00; S, 6.87. Found: C, 53.83; H, 3.63; Cl, 7.72;F, 8.14; N, 6.06; S, 7.02.

Example 141t-Butyl[2-[[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridine-3-carbothioyl]amino]ethyl]carbamate

Under an argon atmosphere, a Lawson reagent (94 mg, 0.233 mmol) wasadded to a toluene (8 ml) solution of thet-butyl[2-[[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridine-3-carbonyl]amino]ethyl]carbamate(120 mg, 0.212 mmol) obtained in Example 138. Under heating underreflux, the resulting mixture was stirred for 1.5 hours. After cooling,the solvent was concentrated under reduced pressure. The residue thusobtained was subjected to flash silica gel column chromatography. Thefraction obtained from the hexane:ethyl acetate=1:1 eluate wasconcentrated to give the title compound (84 mg, 0.144 mmol, 68%) as ayellow amorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 1.46(9H,s), 3.52-3.57(2H,m), 3.82-3.86(2H,m),5.09(1H,brs), 5.99(1H,s), 6.92-6.98(1H,m), 6.99-7.05(1H,m),7.41(2H,d,J=8.6 Hz), 7.55(2H,d,J=8.6 Hz), 7.63(1H,d,J=8.3 Hz),7.89-7.94(1H,m), 8.21(1H,dd,J=8.3,2.2 Hz), 9.06(1H,d,J=2.2 Hz),9.61(1H,brs).

MSm/z: 582(M⁺+H).

Example 142N-(2-Aminoethyl)-6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]thionicotinamide

To an ethanol (3 ml) solution oft-butyl[2-[[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridine-3-carbothioyl]amino]ethyl]carbamate(80 mg, 0.137 mmol) was added concentrated hydrochloric acid (2 ml). Theresulting mixture was stirred at room temperature for 20 minutes. Thereaction mixture was concentrated under reduced pressure. To the residuethus obtained was added ethanol, followed by concentration. Thisoperation was conducted three times to give the title compound (76 mg,0.137 mmol, quant.) as a 1.75 hydrochloride (yellow powder).

¹H-NMR(400 MHz,DMSO-d₆)δ: 3.07-3.12(2H,m), 3.93-3.97(2H,m), 6.46(1H,s),7.20-7.26(1H,m), 7.28-7.34(1H,m), 7.66(2H,d,J=9.0 Hz), 7.69(2H,d,J=9.0Hz), 7.88(1H,d,J=8.3 Hz), 8.05-8.12(1H,m), 8.14(2H,brs),8.24(1H,dd8.3,2.4), 9.05(1H,d,J=2.4 Hz), 10.74(1H,brs).

mp: 164 to 166° C.

Elemental Analysis for C₂₁H₁₈ClF₂N₃O₂S₂.0.5H₂O.1.75HCl: Calculated: C,45.46; H, 3.77; Cl, 17.57; F, 6.85; N, 7.57; S, 11.56. Found: C, 45.02;H, 3.83; Cl, 17.37; F, 6.36; N, 7.54; S, 11.36.

Example 1432-[(4-Chlorophenylthio)(2,5-difluorophenyl)methyl]-6-(1,3-dioxolan-2-yl)pyridine

Under an argon atmosphere, triethylamine (1.77 ml, 12.7 mmol) andmethanesulfonyl chloride (851 μl, 11.0 mmol) were added to adichloromethane solution (30 ml) of the2-[(2,5-difluorophenyl)hydroxymethyl]-6-(1,3-dioxolan-2-yl)pyridine(2.48 g, 8.46 mmol) obtained in Referential Example 32 under icecooling. The resulting mixture was stirred at room temperature for 3.5hours. To the reaction mixture was added a saturated aqueous solution ofsodium bicarbonate, followed by extraction with diethyl ether. Theextract was washed with brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure.

To a dimethylformamide (20 ml) solution of the residue (2.14 g, 5.76mmol) were added 4-chlorobenzenethiol (1.0 g, 6.91 mmol) and potassiumcarbonate (1.19 g, 8.64 mmol). The resulting mixture was stirred at 50°C. for 2 hours. After cooling to room temperature, the reaction mixturewas diluted with diethyl ether. The diluted solution was washedsequentially with water and brine. The organic layer thus obtained wasdried over sodium sulfate, and concentrated under reduced pressure. Theresidue thus obtained was subjected to flash silica gel columnchromatography. The fraction obtained from the hexane:ethyl acetate=5:1eluate was concentrated under reduced pressure to give the titlecompound (2.12 g, 5.05 mmol, 88%) as a pale yellow oil.

¹H-NMR(400 MHz,CDCl₃)δ: 4.06-4.20(4H,m), 5.84(1H,s), 5.89(1H,s),6.86-6.96(2H,m), 7.17(2H,d,J=8.8 Hz), 7.23(2H,d,J=8.8 Hz),7.38(1H,d,J=7.8 Hz), 7.43(1H,d,J=7.8 Hz), 7.44-7.48(1H,m),7.69(1H,t,J=7.8 Hz).

MSm/z: 420 (M⁺+H).

Example 1442-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-6-(1,3-dioxolan-2-yl)pyridine

To a methanol (40 ml) solution of2-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]-6-(1,3-dioxolan-2-yl)pyridine(2.40 g, 5.72 mmol) were added hexaammonium heptamolybdate tetrahydrate(200 mg) and 30% aqueous hydrogen peroxide (20 ml). The resultingmixture was stirred for 5 days. Water was added to the reaction mixtureand the solid thus precipitated was collected by filtration. The residuewas washed with water. The residue was dissolved in ethyl acetate. Theresulting solution was washed sequentially with water and brine. Theorganic layer was concentrated under reduced pressure. The residue waswashed with ethyl acetate to give the title compound (2.09 g, 4.63 mmol,81%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 4.05-4.17(4H,m), 5.73(1H,s), 5.98(1H,s),6.93-7.05(2H,m), 7.41(2H,d,J=8.8 Hz), 7.52(2H,d,J=8.8 Hz),7.50-7.53(1H,m), 7.64(1H,dd,J=7.6,1.0 Hz), 7.80(1H,t,J=7.6 Hz),7.91-7.95(1H,m).

MSm/z: 452(M⁺+H).

Example 145[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbaldehyde

To a 1,4-dioxane (40 ml) solution of2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-6-(1,3-dioxolan-2-yl)pyridine(2.05 g, 4.54 mmol) was added concentrated hydrochloric acid (10 ml).The resulting mixture was stirred at room temperature for 20 hours. Thesolvent was concentrated under reduced pressure. To the residue wasadded ethyl acetate. The resulting mixture was washed sequentially withwater, a saturated aqueous solution of sodium bicarbonate and brine. Theorganic layer thus obtained was dried over magnesium sulfate, andconcentrated under reduced pressure to give the title compound (1.85 g,4.54 mmol, quant.) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 6.05(1H,s), 6.92-6.98(1H,m), 7.02-7.08(1H,m),7.43(2H,d,J=8.8 Hz), 7.58(2H,d,J=8.8 Hz), 7.90(1H,dd,J=7.1,2.0 Hz),7.93-7.99(2H,m), 8.04-8.09(1H,m), 10.00(1H,s).

MSm/z: 408(M⁺+H).

Example 1466-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]picolinic acid

To a formic acid (5 ml) solution of[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbaldehyde(390 mg, 0.956 mmol) was added 30% aqueous hydrogen peroxide (325 μl,2.87 mmol). The resulting mixture was stirred at room temperature for 4hours. Water was added to the reaction mixture, followed by filtration.The residue was washed with water. The resulting residue was dissolvedin ethyl acetate. The resulting solution was washed sequentially with asaturated aqueous solution of ammonium chloride, water and brine. Theorganic layer thus obtained was dried over magnesium sulfate andconcentrated under reduced pressure. The residue thus obtained wasrecrystallized from ethanol to give the title compound (310 mg, 0.731mmol, 77%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 6.01(1H,s), 6.93-6.99(1H,m), 7.04-7.10(1H,m),7.44(2H,d,J=8.6 Hz), 7.61(2H,d,J=8.6 Hz), 7.78-7.82(1H,m),7.99(1H,d,J=7.8 Hz), 8.06(1H,t,J=7.8 Hz), 8.26(1H,d,J=7.8 Hz).

mp: 200 to 201° C.

Elemental Analysis for C₁₉H₁₂ClF₂NO₄S: Calculated: C, 53.84; H, 2.85;Cl, 8.37; F, 8.97; N, 3.30; S, 7.57. Found: C, 53.55; H, 2.80; Cl, 8.23;F, 9.00; N, 3.55; S, 7.68.

Example 147[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl](4-methylpiperazin-1-yl)methanone

To a dichloromethane (5 ml) solution of6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]picolinic acid(130 mg, 0.307 mmol) were added N-methylmorpholine (41 μl, 0.368 mmol),1-hydroxybenzotriazole (13 mg, 0.368 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (71 mg,0.368 mmol) and 1-methylpiperazine (40 μl, 0.368 mmol). The resultingmixture was stirred at room temperature for 15 hours. The reactionmixture was diluted with dichloromethane. The diluted mixture was washedsequentially with water, a saturated aqueous solution of sodiumbicarbonate and brine. The organic layer thus obtained was dried overmagnesium sulfate, and concentrated under reduced pressure. The residuethus obtained was subjected to flash silica gel column chromatography.The fraction obtained from the dichloromethane:methanol=30:1 eluate wasconcentrated under reduced pressure to give the title compound (40 mg,0.0791 mmol, 26%) as a white amorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 2.36(3H,s), 2.44-2.65(4H,m), 3.48-4.00(4H,m),5.91(1H,s), 6.87-6.94(1H,m), 6.98-7.05(1H,m), 7.41(2H,d,J=7.8 Hz),7.55-7.60(3H,m), 7.74(1H,d,J=7.3 Hz), 7.85(1H,t,J=7.6 Hz),8.06-8.13(1H,m).

FAB-MS: 506.1085 (Calcd for C₂₄H₂₃ClF₂N₃O₃S: 506.1117).

Example 148t-Butyl[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbamate

Under an argon atmosphere, diphenylphosphoryl azide (428 μl, 2.00 mmol)and triethylamine (394 μl, 2.83 mmol) were added to a solution of the6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]picolinic acid(600 mg, 1.42 mmol) obtained in Example 146 in a mixture of butanol (2ml) and toluene (10 ml). The resulting mixture was stirred for 23 hoursunder heating and refluxing. The reaction mixture was washed with brine.The organic layer thus obtained was dried over magnesium sulfate, andthen concentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate=4:1 eluate was concentrated underreduced pressure to give the title compound (380 mg, 0.768 mmol, 54%) asa pale yellow amorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 1.54(9H,s), 5.76(1H,s), 6.90-6.95(1H,m),6.99-7.05(1H,m), 7.14(1H,d,J=7.3 Hz), 7.19(1H,brs), 7.40(2H,d,J=8.8 Hz),7.55(2H,d,J=8.8 Hz), 7.65(1H,dd,J=8.3,7.3 Hz), 7.95(1H,d,J=8.3 Hz),8.01-8.05(1H,m).

MSm/z: 495(M⁺+H).

Example 1496-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-ylamine

To an ethanol (5 ml) solution oft-butyl[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbamate(370 mg, 0.748 mmol) was added concentrated hydrochloric acid (5 ml).The resulting mixture was stirred at room temperature for 6 hours. Thereaction mixture was concentrated under reduced pressure. To the residuethus obtained was added ethyl acetate. The resulting mixture was washedsequentially with saturated sodium bicarbonate and brine. The organiclayer thus obtained was dried over magnesium sulfate and concentratedunder reduced pressure to give the title compound (210 mg, 0.537 mmol,71%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 4.46(2H,brs), 5.72(1H,s), 6.45(1H,d,J=8.1 Hz),6.88(1H,d,J=7.3 Hz), 6.91-7.03(2H,m), 7.39(2H,d,J=8.6 Hz),7.39-7.43(1H,m), 7.56(2H,d,J=8.6 Hz), 7.98-8.03(1H,m).

mp: 183 to 184° C.

Elemental Analysis for C₁₈H₁₃ClF₂N₂O₂S: Calculated: C, 54.76; H, 3.32;Cl, 8.98; F, 9.62; N, 7.10; S, 8.12. Found: C, 54.46; H, 3.22; Cl, 8.82;F, 9.55; N, 7.07; S, 8.11.

Example 150N-[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]-2-(pyridin-2-yl)acetamide

To a dichloromethane (5 ml) solution of6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-ylamine(74 mg, 0.187 mmol) were added N-methylmorpholine (90 μl, 0.818 mmol),1-hydroxybenzotriazole (11 mg, 0.313 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60 mg,0.312 mmol) and 2-pyridylacetic acid hydrochloride (54 mg, 0.312 mmol).The resulting mixture was stirred at room temperature for 24 hours. Thereaction mixture was diluted with dichloromethane. The diluted solutionwas washed sequentially with water, a saturated aqueous solution ofsodium bicarbonate and brine. The organic layer thus obtained was driedover magnesium sulfate, and concentrated under reduced pressure. Theresidue thus obtained was subjected to flash silica gel columnchromatography. The fraction obtained from the hexane:ethyl acetate=4:1eluate was concentrated under reduced pressure to give the titlecompound (48 mg, 0.0934 mmol, 50%) as a white amorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 3.86(1H,d,J=15.9 Hz), 3.95(1H,d,J=15.9 Hz),5.82(1H,s), 6.92-6.96(1H,m), 6.98-7.08(1H,m), 7.21(1H,d,J=7.6 Hz),7.25-7.33(3H,m), 7.39(2H,d,J=8.5 Hz), 7.54(2H,d,J=8.5 Hz),7.66-7.73(2H,m), 8.07-8.11(1H,m), 8.20(1H,d,J=8.6 Hz), 8.69(1H,d,J=4.4Hz).

FAB-MS: 514.0800 (Calcd for C₂₅H₁₉ClF₂N₃O₃S: 514.0804).

Example 151(E)-2-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-6-(2-pyridin-2-ylvinyl)pyridine

To a 1,4-dioxane (5 ml) solution of the6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbaldehyde(100 mg, 0.245 mmol) obtained in Example 145 were addedtriphenyl(2-pyridylmethyl)phosphonium chloride hydrochloride (336 mg,0.773 mmol) and triethylamine (215 μl, 1.55 mmol). The resulting mixturewas stirred at room temperature for 5 hours. After the reaction mixturewas concentrated, ethyl acetate was added to the concentrate. Theresulting mixture was washed sequentially with water and brine. Theorganic layer was dried over magnesium sulfate and concentrated underreduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=4:1 eluate was concentrated under reduced pressureto give the title compound (202 mg, 0.418 mmol, 81%) as a colorlessamorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 5.99(1H,s), 6.98-7.08(2H,m), 7.21-7.25(1H,m),7.37-7.48(6H,m), 7.54(2H,d,J=8.1 Hz), 7.64(1H,d,J=15.4 Hz),7.69-7.75(2H,m), 8.04-8.09(1H,m), 8.65 (1H, d, J=4.4 Hz).

FAB-MS: 483.0739 (Calcd for C₂₅HlBClF₂N₂O₂S: 483.0746).

Example 1522-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-6-(2-pyridin-2-ylethyl)pyridine

To a mixed solution of(E)-2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-6-(2-pyridin-2-ylvinyl)pyridine(180 mg, 0.373 mmol) in ethanol (5 ml) and 1,4-dioxane (2 ml) was addedan ethanol suspension (1 ml) of Raney nickel. Under a hydrogenatmosphere of 1 atmospheric pressure, the resulting mixture wasvigorously stirred for 1.5 hours. After filtration of the reactionmixture, the filtrate was concentrated under reduced pressure. Theresidue thus obtained was subjected to flash silica gel columnchromatography. The fraction obtained from the hexane:ethyl acetate=3:2eluate was concentrated under reduced pressure, followed byrecrystallization from hexane:ethyl acetate to give the title compound(110 mg, 0.227 mmol, 61%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 3.13-3.23(4H,m), 5.92(1H,s), 6.93-7.06(2H,m),7.07-7.12(3H,m), 7.37-7.40(3H,m), 7.52-7.60(4H,m), 8.05-8.09(1H,m),8.52(1H,d,J=3.7 Hz).

mp: 88 to 89° C.

Elemental Analysis for C₂₅H₁₉ClF₂N₂O₂S: Calculated: C, 61.92; H, 3.95;Cl, 7.31; F, 7.84; N, 5.78; S, 6.61. Found: C, 61.84; H, 4.08; Cl, 7.26;F, 7.69; N, 5.90; S, 6.75.

Example 1533-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-1-(3-hydroxypropyl)piperidin-2-one

Under an argon atmosphere, n-butyl lithium (a 1.56M hexane solution,0.140 ml, 0.218 mmol) was added at −78° C. to a 1,2-dimethoxyethanesolution (2 ml) of the2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (63.0 mg, 0.208mmol) obtained in Referential Example 1. The resulting mixture wasstirred at −78° C. for 5 minutes. After addition of the3-bromo-1-[3-(t-butyldimethylsilyloxy)propyl]piperidin-2-one (72.8 mg,0.208 mmol) obtained in Referential Example 34, the resulting mixturewas stirred at room temperature for 15 hours. The reaction mixture wascooled to 0° C. After addition of water, the resulting mixture wasextracted with ethyl acetate. The extract was washed with water andbrine, dried over magnesium sulfate and concentrated. The residue thusobtained was purified by flash silica gel column chromatography(hexane:ethyl acetate=4:1) to give a low polar silyl-protected compound(30.0 mg) and a high polar silyl-protected compound (30.0 mg), each as acolorless oil. The resulting high polar silyl-protected compound (30.0mg) was dissolved in tetrahydrofuran (3 ml), followed by the addition ofhydrogen fluoride-pyridine (0.5 ml). The resulting mixture was stirredat room temperature for 3 hours. After dilution with ethyl acetate, thediluted mixture was washed with water brine, dried over magnesiumsulfate and concentrated. The residue thus obtained was subjected tosilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=2:3 eluate was concentrated to yield a white solid.The resulting solid was recrystallized from ethyl acetate-hexane to givethe title compound (11.8 mg, 0.0258 mmol, 12%) as colorless needlecrystals.

¹H-NMR(400 MHz,CDCl₃)δ: 1.50-1.60(2H,m), 1.88-2.08(3H,m),2.70-2.77(1H,m), 2.86-2.93(1H,m), 3.20-3.36(5H,m),3.62(1H,ddd,J=13.7,9.0,4.6 Hz), 3.70-3.78(1H,m), 5.71-5.73(1H,m),6.86(1H,td,J=9.0,4.6 Hz), 6.96-7.02(1H,m), 7.37(2H,d,J=8.8 Hz),7.55-7.62(3H,m).

mp: 120 to 121° C.

FAB-MS: 458.0966 (Calcd for C₂₁H₂₃ClF₂NO₄S: 458.1004).

Example 154 t-Butyl3-[[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]propionate

In a small amount of a saturated aqueous solution of potassium carbonatewas dissolved β-alanine t-butyl ester hydrochloride (1.5 g), followed byextraction with methylene chloride. The extract was dried andconcentrated into 720 mg of β-alanine t-butyl ester in the free form.The resulting ester and a 1,4-dioxane (2.0 ml) solution of the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(300 mg, 0.72 mmol) obtained in Example 54 was stirred at 120° C. for 4days under an argon atmosphere. After cooling to room temperature, thereaction mixture was diluted with ethyl acetate. The diluted mixture waswashed with water and brine, dried and then concentrated under reducedpressure. The residue thus obtained was purified by silica gelchromatography (hexane:ethyl acetate=5:1) to give the title compound (79mg, 16%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 1.46(9H,s), 2.52(2H,t,J=6.0 Hz), 3.58(2H,q,J=6.0Hz), 4.95(1H,br), 5.96(1H,s), 6.68(1H,s), 6.9-7.05(2H,m), 7.11(1H,m),7.22(2H,d,J=8.4 Hz), 7.23(2H,d,J=8.4 Hz), 8.02(1H,s).

MS: 525(M⁺+H).

Example 1553-[[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]propionicacid

To a methanol (6 ml) solution of t-butyl3-[[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]propionate(79 mg) was added hexaammonium heptamolybdate tetrahydrate (30 mg). Tothe resulting mixture was added 30% aqueous hydrogen peroxide (3 ml) andthe mixture was stirred for 16 hours. The reaction mixture was dilutedwith ethyl acetate (60 ml). The diluted mixture was washed with waterand brine and concentrated under reduced pressure. To the residue thusobtained was added trifluoroacetic acid (1.0 ml). The resulting mixturewas stirred for 1 hour. From the reaction mixture, trifluoroacetic acidwas distilled off under reduced pressure. The residue was dissolved inwater-ethanol (1:1). The resulting solution was basified by the additionof a saturated aqueous solution (0.2 ml) of sodium bicarbonate thereto.An aqueous solution of sodium bisulfate was added and the resultingmixture was extracted with ethyl acetate (80 ml). The extract was washedwith brine, dried and concentrated under reduced pressure. The residuewas crystallized in ether to give the title compound (61 mg, 81%) as a0.5 hydrate.

¹H-NMR(400 MHz,CDCl₃)δ: 2.76(2H,m), 3.72(2H,m), 6.11(1H,s), 6.92(1H,m),7.04(1H,m), 7.44(2H,d,J=8.8 Hz), 7.46(1H,s), 7.48(1H,m), 7.61(2H,d,J=8.8Hz), 7.94(1H,s).

mp: 200 to 205° C.

Elemental Analysis for C₂₁H₁₆Cl₂F₂N₂O₄S.0.5H₂O: Calculated: C, 49.42; H,3.36; N, 5.49; S, 6.28; Cl, 13.89; F, 7.44. Found: C, 49.51; H, 3.28; N,5.52; S, 6.35; Cl, 13.75; F, 7.77.

Example 1562-[[5-Chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl](methyl)amino]ethanol

A 1,4-dioxane (2.0 ml) solution of the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(200 mg, 0.48 mmol) obtained in Example 54 and methylaminoethanol (200μl) was stirred at 110° C. for 3 days under an argon atmosphere. Aftercooling to room temperature, the reaction mixture was concentrated underreduced pressure. The residue thus obtained was purified by silica gelchromatography (hexane:ethyl acetate=3:1) to give the title compound(164 mg, 75%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 3.07(3H,s), 3.73(2H,d,J=4.8 Hz), 3.85(2H,d,J=4.8Hz), 5.99(1H,s), 6.86(1H,s), 6.91-7.12(3H,m), 7.23(2H,d,J=8.8 Hz),7.25(2H,d,J=8.8 Hz), 8.00(1H,s).

MSm/z: 455(M⁺+H).

Example 1575-Chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]-2-[2-(pyridin-2-yl)ethylamino]pyridine

A 1,4-dioxane (1.5 ml) solution of the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(150 mg, 0.36 mmol) obtained in Example 54 and 2-pyridin-2-ylethylamine(400 μl) was stirred at 120° C. for 5 days under an argon atmosphere.After cooling to room temperature, the reaction mixture was concentratedunder reduced pressure. The residue thus obtained was purified by silicagel chromatography (hexane:ethyl acetate=1:1) to give the title compound(126 mg, 70%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 3.07(2H,d,J=6.4 Hz), 3.71(2H,q,J=6.4 Hz),5.24(1H,br), 5.96(1H,s), 6.69(1H,s), 6.93-7.30(9H,m),7.61(1H,dt,J=2.0,7.6 Hz), 8.01(1H,s), 8.56(1H,m).

MSm/z: 502(M⁺+H).

Example 1585-Chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]-2-[3-(imidazol-1-yl)propylamino]pyridine

A 1,4-dioxane (1.5 ml) solution of the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(200 mg, 0.48 mmol) obtained in Example 54 and3-(imidazol-1-yl)propylamine (400 μl) was stirred at 120° C. for 5 daysunder an argon atmosphere. After cooling to room temperature, thereaction mixture was concentrated under reduced pressure. The residuethus obtained was purified by silica gel chromatography (hexane:ethylacetate=1:1) to give the title compound (94 mg, 39%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 2.11(2H,m), 3.35(2H,m), 4.11(2H,d,J=6.8 Hz),4.86(1H,m), 5.94(1H,s), 6.69(1H,s), 6.96(1H,s), 6.95-7.26(3H,m),7.12(1H,s), 7.21(2H,d,J=8.8 Hz), 7.23(2H,d,J=8.8 Hz), 7.92(1H,m),8.02(1H,s).

MSm/z: 505(M⁺+H).

Example 1592-[[5-Chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]ethanol

A 1,4-dioxane (1.5 ml) solution of the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(180 mg, 0.43 mmol) obtained in Example 54 and 2-aminoethanol (300 μl)was stirred at 120° C. for 64 hours under an argon atmosphere. Aftercooling to room temperature, the reaction mixture was concentrated underreduced pressure. The residue thus obtained was purified by silica gelchromatography (hexane:ethyl acetate=1:1) to give the title compound(106 mg, 56%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 3.00(1H,br), 3.51(2H,br), 3.81(2H,d,J=4.8 Hz),5.05(1H,br), 5.95(1H,s), 6.74(1H,s), 6.92-7.06(2H,m), 7.13(1H,m),7.23(4H,s), 7.99(1H,s).

MSm/z: 441(M⁺+H).

Example 1601-[3-[[5-Chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]propyl]pyrrolidin-2-one

A 1,4-dioxane (1.5 ml) solution of the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(200 mg, 0.48 mmol) obtained in Example 54 and1-(3-aminopropyl)pyrrolidin-2-one (400 μl) was stirred at 120° C. for 17hours under an argon atmosphere. After cooling to room temperature, thereaction mixture was concentrated under reduced pressure. The residuethus obtained was purified by silica gel chromatography (hexane:ethylacetate=1:1) to give the title compound (68 mg, 27%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 1.77(2H,m), 2.04(2H,m), 2.41(2H,m),3.30-3.40(6H,m), 5.53(1H,br), 5.94(1H,s), 6.72(1H,s), 6.90-7.03(2H,m),7.13(1H,m), 7.22(2H,d,J=8.0 Hz), 7.25(2H,d,J=8.0 Hz), 7.99(1H,s).

MSm/z: 522(M⁺+H).

Example 161 t-Butyl4-[[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]piperidine-1-carboxylate

A 1,4-dioxane (2.2 ml) solution of the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(300 mg, 0.48 mmol) obtained in Example 54 and t-butyl4-aminopiperidine-1-carboxylate (600 mg) was stirred at 120° C. for 5days under an argon atmosphere. After cooling to room temperature, thereaction mixture was concentrated under reduced pressure. The residuethus obtained was purified by silica gel chromatography (hexane:ethylacetate=3:1) to give the title compound (36 mg, 9%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 1.34(2H,m), 1.47(9H,s), 1.98(2H,m), 2.94(2H,m),3.79(1H,m), 4.11(2H,m), 4.58(1H,br), 5.95(1H,s), 6.63(1H,s),6.93-7.04(2H,m), 7.12(1H,m), 7.22(4H,s), 8.01(1H,s).

MSm/z: 580(M⁺+H).

Example 162 t-Butyl3-[[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]propylcarbamate

A 1,4-dioxane (1.5 ml) solution of the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(300 mg, 0.48 mmol) obtained in Example 54 andt-butyl(3-aminopropyl)carbamate (400 μl) was stirred at 120° C. for 2days under an argon atmosphere. After cooling to room temperature, thereaction mixture was concentrated under reduced pressure. The residuethus obtained was purified by silica gel chromatography (hexane:ethylacetate=1:1) to give the title compound (71 mg, 27%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 1.45(9H,s), 1.73(2H,m), 3.21(2H,m), 3.38(2H,m),4.85(1H,br), 5.10(1H,br), 5.95(1H,s), 6.96-7.04(2H,m), 7.12(1H,m),7.22(2H,d,J=8.8 Hz), 7.24(2H,d,J=8.8 Hz), 8.00(1H,s).

MSm/z: 554(M⁺+H).

Example 1635-Chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]-2-[(2-methylthioethyl)amino]pyridine

A 1,4-dioxane (1.5 ml) solution of the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(200 mg, 0.48 mmol) obtained in Example 54 and 2-methylthioethylamine(200 μl) was stirred at 120° C. for 2 days under an argon atmosphere.After cooling to room temperature, the reaction mixture was concentratedunder reduced pressure. The residue thus obtained was purified by silicagel chromatography (hexane:ethyl acetate=3:1) to give the title compound(29 mg, 13%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 2.12(3H,s), 2.74(2H,d,J=6.4 Hz), 3.52(2H,m),4.98(1H,br), 5.96(1H,s), 6.69(1H,s), 6.92-7.05(2H,m), 7.13(1H,m),7.23(4H,m), 8.02(1H,s).

MSm/z: 471(M⁺+H).

Example 1642-[[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl](methyl)amino]ethanol

To a methanol (6 ml) solution of the2-[[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl](methyl)amino]ethanol(160 mg, 0.35 mmol) obtained in Example 156 was added hexaammoniumheptamolybdate tetrahydrate (30 mg), followed by further addition of 30%aqueous hydrogen peroxide (3 ml). The resulting mixture was stirred for17 hours. The reaction mixture was diluted with ethyl acetate (60 ml).The diluted mixture was washed with water and brine, and concentratedunder reduced pressure. The residue thus obtained was purified by silicagel chromatography (hexane:ethyl acetate=2:1), followed bycrystallization from hexane-ethanol to give the title compound (162 mg,95%) as needle crystals.

¹H-NMR(400 MHz,CDCl₃)δ: 3.20(3H,s), 3.7-3.85(2H,m), 3.89(2H,m),6.14(1H,s), 6.94(1H,m), 7.04(1H,m), 7.42(1H,br), 7.44(2H,d,J=8.8 Hz),7.52(1H,m), 7.62(2H,d,J=8.8 Hz), 7.99(1H,s).

mp: 88 to 89° C.

Elemental Analysis for C₂₁H₁₈Cl₂F₂N₂O₃S_(0.5)H₂O: Calculated: C, 50.82;H, 3.86; N, 5.64; S, 6.46; Cl, 14.29; F, 7.66. Found: C, 51.16; H, 3.66;N, 5.78; S, 6.62; Cl, 14.32; F, 7.73.

Example 1652-[[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl](methyl)amino]ethylethylcarbamate

To a methylene chloride (1.0 ml) solution of2-[[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl](methyl)amino]ethanol(73 mg, 0.15 mmol) was added pyridine (0.5 ml), followed by furtheraddition of ethyl isocyanate (100 μl). The resulting mixture was stirredfor 19 hours. After the reaction mixture was concentrated under reducedpressure, the residue thus obtained was purified by silica gelchromatography (hexane:ethyl acetate=3:1) to yield the title compound(65 mg, 74%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 1.06(3H,t,J=7.2 Hz), 3.19(3H,s), 3.20(2H,m),3.68(1H,m), 3.91(1H,m), 4.25(1H,m), 4.40(1H,m), 5.15(1H,br), 6.16(1H,s),6.92(1H,m), 7.03(1H,m), 7.45(2H,d,J=8.4 Hz), 7.49(1H,s), 7.55(1H,m),7.60(2H,d,J=8.4 Hz), 8.03(1H,s).

EI-MS: 557.0714 (Calcd for C₂₄H₂₃Cl₂F₂N₃O₄S: 557.0754).

Example 1665-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]-2-[2-(pyridin-2-yl)ethylamino]pyridine

To a methanol (6 ml) solution of the5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]-2-[2-(pyridin-2-yl)ethylamino]pyridine(120 mg, 0.35 mmol) obtained in Example 157 was added hexaammoniumheptamolybdate tetrahydrate (30 mg), followed by further addition of 30%aqueous hydrogen peroxide (3 ml). The resulting mixture was stirred for2 days. The reaction mixture was diluted with ethyl acetate (80 ml). Thediluted mixture was washed with water and brine and concentrated underreduced pressure. The residue thus obtained was purified by silica gelchromatography (hexane:ethyl acetate=3:1) to give the title compound (43mg, 33%) as an amorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 3.19(2H,t,J=5.2 Hz), 3.81(2H,m), 5.51(1H,br),6.13(1H,s), 6.91(1H,m), 7.03(1H,m), 7.20-7.30(3H,m), 7.43(2H,d,J=8.8Hz), 7.50(1H,m), 7.62(2H,d,J=8.8 Hz), 7.68(1H,s), 7.98(1H,s),8.60(1H,m).

FAB-MS: 534.0651 (Calcd for C₂₅H₂₀Cl₂F₂N₃O₂S: 534.0621).

Example 1675-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]-2-[3-(imidazol-1-yl)propylamino]pyridine

To a methanol (6 ml) solution of the5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]-2-[3-(imidazol-1-yl)propylamino]pyridine(94 mg, 0.19 mmol) obtained in Example 158 was added hexaammoniumheptamolybdate tetrahydrate (30 mg), followed by the addition of 30%aqueous hydrogen peroxide (3 ml). The resulting mixture was stirred for17 hours. After the reaction mixture was diluted with ethyl acetate (80ml), the diluted mixture was washed with water and brine, andconcentrated under reduced pressure. The residue thus obtained waspurified by silica gel chromatography (7% methanol-chloroform) to givethe title compound (5 mg, 5%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 2.20(2H,m), 3.44(2H,m), 4.32(2H,m), 5.77(1H,br),6.13(1H,s), 6.91(1H,m), 7.02(1H,m), 7.10(1H,s), 7.30(1H,s), 7.40(1H,s),7.44(2H,d,J=8.4 Hz), 7.54(1H,m), 7.65(2H,d,J=8.4 Hz), 7.97(s,1H),8.05(1H,s), 8.89(1H,s).

FAB-MS: 537.0737 (Calcd for C₂₄H₂₁Cl₂F₂N₄O₂S: 537.0730).

Example 1682-[[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]ethanol

To a methanol (6 ml) solution of the2-[[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]ethanol(143 mg, 0.33 mmol) obtained in Example 159 was added hexaammoniumheptamolybdate tetrahydrate (30 mg), followed by further addition of 30%aqueous hydrogen peroxide (3 ml). The resulting mixture was stirred for17 hours. After the reaction mixture was diluted with ethyl acetate (60ml), the diluted solution was washed with water and brine, andconcentrated under reduced pressure. The residue thus obtained waspurified by silica gel chromatography (hexane:ethyl acetate=1:1) andcrystallized from ethanol to give the title compound (98 mg, 63%) asneedle crystals.

¹H-NMR(400 MHz,CDCl₃)δ: 3.60(2H,m), 3.87(2H,m), 5.53(1H,br), 6.11(1H,s),6.92(1H,m), 7.03(1H,m), 7.40(1H,s), 7.45(2H,d,J=8.8 Hz), 7.48(1H,m),7.61(2H,d,J=8.8 Hz), 7.96(1H,s). mp: 168 to 169° C.

Elemental Analysis for C₂₀H₁₆Cl₂F₂N₂O₃S: Calculated: C, 50.75; H, 3.41;N, 5.92; S, 6.77; Cl, 14.98; F, 8.03. Found: C, 50.33; H, 3.40; N, 5.95;S, 6.90; Cl, 14.93; F, 8.04.

Example 1691-[3-[[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]propyl]pyrrolidin-2-one

To a methanol (6 ml) solution of the1-[3-[[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]propyl]pyrrolidin-2-one(143 mg, 0.33 mmol) obtained in Example 160 was added hexaammoniumheptamolybdate tetrahydrate (30 mg), followed by the addition of 30%aqueous hydrogen peroxide (3 ml). The resulting mixture was stirred for17 hours. After the reaction mixture was diluted with ethyl acetate (60ml), the diluted mixture was washed with water and brine, andconcentrated under reduced pressure. The residue thus obtained waspurified by silica gel chromatography (2% methanol-ethyl acetate) andcrystallized from ether to give the title compound (42 mg, 60%) asneedle crystals.

¹H-NMR(400 MHz,CDCl₃)δ: 1.82(2H,m), 2.05(2H,m), 2.43(2H,m),3.35-3.50(6H,m), 5.53(1H,br), 6.12(1H,s), 6.92(1H,m), 7.02(1H,m),7.23(1H,s), 7.42(2H,d,J=8.4 Hz), 7.53(1H,m), 7.62(2H,d,J=8.4 Hz),7.96(1H,s).

mp: 78 to 80° C.

Elemental Analysis for C₂₅H₂₃Cl₂F₂N₃O₃S: Calculated: C, 54.16; H, 4.18;N, 7.58; S, 5.78; Cl, 12.79; F, 6.85. Found: C, 54.15; H, 4.37; N, 7.39;S, 5.60; Cl, 12.20; F, 6.64.

Example 170 t-Butyl4-[[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]piperidine-1-carboxylate

To a methanol (6 ml) solution of the t-butyl4-[[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]piperidine-1-carboxylate(41 mg, 0.070 mmol) obtained in Example 161 was added hexaammoniumheptamolybdate tetrahydrate (30 mg), followed by further addition of 30%aqueous hydrogen peroxide (3 ml). The resulting mixture was stirred for20 hours. After dilution with ethyl acetate (80 ml), the diluted mixturewas washed with water and brine, and concentrated under reducedpressure. The residue was purified by silica gel chromatography(hexane:ethyl acetate=4:1) to give the title compound (41 mg, 95%) as anoil.

¹H-NMR(400 MHz,CDCl₃)δ: 1.43(2H,m), 1.47(9H,s), 2.04(2H,m), 2.97(2H,m),3.88(1H,m), 4.08(2H,m), 6.08(1H,s), 6.89(1H,m), 7.02(1H,m), 7.25(1H,s),7.43(2H,d,J=8.0 Hz), 7.46(1H,m), 7.58(2H,d,J=8.0 Hz), 7.96(1H,s).

MSm/z: 612(M⁺+H).

Example 1714-[[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]piperidinedihydrochloride

To t-butyl4-[[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]piperidine-1-carboxylate(41 mg, 0.067 mmol) was added a 20% hydrochloric acid-methanol solution.The resulting mixture was stirred for 2 hours. The reaction mixture wasconcentrated under reduced pressure. The residue thus obtained wasdissolved in chloroform, followed by further concentration. Theamorphous substance thus obtained was dried under reduced pressure toafford the title compound (34 mg, 84%).

¹H-NMR(400 MHz,CD₃OD)δ: 1.90(2H,m), 2.33(2H,m), 3.22(2H,m), 3.52(2H,m),4.10(1H,m), 6.28(1H,s), 7.09(1H,m), 7.23(1H,m), 7.53(1H,m),7.61(2H,d,J=6.4 Hz), 7.75(2H,d,J=6.4 Hz), 7.89(1H,s), 8.05(1H,s).

Elemental Analysis for C₂₃H₂₁Cl₂F₂N₃O₂S.2HCl.H₂O: Calculated: C, 45.79;H, 4.18; N, 6.96; S, 5.31; Cl, 23.50; F, 6.30. Found: C, 45.48; H, 4.17;N, 7.2; S, 5.24; Cl, 22.82; F, 6.02.

Example 172 t-Butyl3-[[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]propylcarbamate

To a methanol (6 ml) solution of the t-butyl3-[[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]propylcarbamate(70 mg, 0.13 mmol) obtained in Example 162 was added hexaammoniumheptamolybdate tetrahydrate (30 mg), followed by further addition of 30%aqueous hydrogen peroxide (3 ml). The resulting mixture was stirred for20 hours. After dilution with ethyl acetate (80 ml), the diluted mixturewas washed with water and brine, and concentrated under reducedpressure. The residue thus obtained was purified by silica gelchromatography (hexane:ethyl acetate=2:1) to give the title compound (61mg, 82%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 1.45(9H,s), 1.77(2H,m), 3.23(2H,m), 3.42(2H,m),4.89(1H,br), 5.36(1H,br), 6.10(1H,s), 6.90(1H,m), 7.02(1H,m),7.24(1H,s), 7.42(2H,d,J=8.8 Hz), 7.49(1H,m), 7.59(2H,d,J=8.8 Hz),7.95(1H,s).

MSm/z: 586(M⁺+H).

Example 173N-[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]propane-1,3-diaminedihydrochloride

To t-butyl3-[[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]propylcarbamate(70 mg, 0.13 mmol) was added a 20% hydrochloric acid-methanol solution(2 ml). The resulting mixture was stirred for 2 hours. The residueobtained by concentrating the reaction mixture under reduced pressurewas crystallized from ethanol to give the title compound as a whitesolid (42 mg, 83%).

¹H-NMR(400 MHz,DMSO-d₆)δ: 1.83(2H,m), 2.87(2H,m), 3.33(2H,m),6.16(1H,s), 7.28(1H,m), 7.36(1H,s), 7.38(1H,m), 7.52(1H,m),7.69(2H,d,J=8.4 Hz), 7.74(2H,d,J=8.4 Hz), 8.05(1H,s).

mp: 193 to 195° C.

Elemental Analysis for C₂₁H₁₉Cl₂F₂N₃O₂S₂HCl: Calculated: C, 45.10; H,3.78; N, 7.51; S, 5.73; Cl, 25.36; F, 6.79. Found: C, 44.55; H, 3.74; N,7.52; S, 5.73; Cl, 25.09; F, 6.73.

Example 174N-[3-[[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]propyl]acetamide

To a methylene chloride solution (5.0 ml) ofN-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]propane-1,3-diaminedihydrochloride (47 mg, 0.084 mmol) were added pyridine (17 μl, 0.34mmol) and acetic anhydride (9.5 μl, 0.10 mmol). The resulting mixturewas stirred for 1 hour. The residue obtained by concentrating thereaction mixture was purified by silica gel chromatography (ethylacetate:methanol=10:1) to give the title compound (35 mg, 79%). Thecompound was crystallized in ether to afford a white solid (27 mg).

¹H-NMR(400 MHz,CDCl₃)δ: 1.80(2H,m), 2.02(3H,s), 3.36(2H,m), 3.45(2H,m),5.25(1H,br), 6.12(1H,s), 6.15(1H,m), 6.93(1H,m), 7.04(1H,m),7.44(2H,d,J=8.8 Hz), 7.50(1H,m), 7.62(2H,d,J=8.8 Hz), 7.97(1H,s).

mp: 103 to 105° C.

FAB-MS: 528.0740 (Calcd for C₂₃H₂₂Cl₂F₂N₃O₃S: 528.0727).

Example 175N-[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]-N′-(pyrimidin-2-yl)propane-1,3-diamine

To a 1,4-dioxane solution (1.0 ml) of theN-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]propane-1,3-diaminedihydrochloride (76 mg, 0.136 mmol) obtained in Example 173 were addedtriethylamine (76 μl, 0.54 mmol) and 2-chloropyrimidine (23 mg, 0.20mmol). The resulting mixture was stirred at 80° C. for 19 hours. Thereaction mixture was allowed to cool to room temperature, followed bydilution with ethyl acetate. The diluted mixture was washed with waterand brine, dried and concentrated. The residue thus obtained waspurified by silica gel chromatography (hexane:ethyl acetate=1:2) to givethe title compound (50 mg, 65%). The compound was crystallized inethanol to afford a white solid (36 mg).

¹H-NMR(400 MHz,CDCl₃)δ: 1.94(2H,m), 3.48(2H,m), 3.59(2H,m), 5.33(1H,br),5.60(1H,br), 6.12(1H,s), 6.56(1H,t,J=4.8 Hz), 6.92(1H,m), 7.03(1H,m),7.24(1H,s), 7.44(2H,d,J=8.0 Hz), 7.51(1H,m), 7.61(2H,d,J=8.0 Hz),8.00(1H,s), 8.32(1H,d,J=4.8 Hz).

mp: 176 to 178° C.

FAB-MS: 564.0811 (Calcd for C₂₅H₂₂Cl₂F₂N₅O₂S: 564.0839).

Example 1765-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]-2-[(2-methylsulfonylethyl)amino]pyridine

To a methanol (3 ml) solution of the5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]-2-[(2-methylthioethyl)amino]pyridine(29 mg, 0.061 mmol) obtained in Example 163 was added hexaammoniumheptamolybdate tetrahydrate (15 mg), followed by further addition of 30%aqueous hydrogen peroxide (1.5 ml). The resulting mixture was stirredfor 20 hours. After dilution with ethyl acetate (80 ml), the dilutedmixture was washed with water and brine, and concentrated under reducedpressure. The residue thus obtained was purified by silica gelchromatography (hexane:ethyl acetate=1:1), followed by crystallizationfrom ether to give the title compound (24 mg, 73%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 2.98(3H,s), 3.37(2H,t,J=6.0 Hz), 3.94(2H,m),5.38(1H,m), 6.10(1H,s), 6.90(1H,m), 7.01(1H,m), 7.32(1H,s),7.42(2H,d,J=8.8 Hz), 7.45(1H,m), 7.59(2H,d,J=8.8 Hz), 8.00(1H,s).

mp: 134 to 136° C.

Elemental Analysis for C₂₁H₁₈Cl₂F₂N₂O₄S: Calculated: C, 47.11; H, 3.39;N, 5.23; S, 11.98. Found: C, 46.80; H, 3.35; N, 5.30; S, 11.84.

Example 1772,5-Dichloro-4-[(2,5-difluorophenyl)-(4-fluorophenylthio)methyl]pyridine

The 2,5-dichloro-4-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (1.22 g,4.8 mmol) obtained in Referential Example 24 was dissolved in thionylchloride (5.0 ml). To the resulting solution was added a catalyticamount of dimethylformamide. The resulting mixture was stirred for 4hours.

The reaction mixture was concentrated under reduced pressure. To theresidue thus obtained was added 1,4-dioxane, followed by furtherconcentration. The residue was dissolved in dimethylformamide (10 ml).To the resulting solution were added 4-fluorobenzenethiol (730 mg, 5.7mmol) and potassium carbonate (2.07 g, 15 mmol). Under a nitrogenatmosphere, the resulting solution was stirred at room temperature for24 hours. To the reaction mixture was added diethyl ether (120 ml). Theresulting mixture was washed with water and brine. The organic layer wasdried over magnesium sulfate, and concentrated under reduced pressure.The residue was crystallized in ethanol to give the title compound (950mg, 49%) as colorless needle crystals.

¹H-NMR(400 MHz,CDCl₃)δ: 5.92(1H,s), 6.94-7.04(4H,m), 7.19(1H,m),7.33-7.4(2H,m), 7.57(1H,s), 8.33(1H,s).

mp: 95 to 97° C.

MSm/z: 400(M⁺+1)

Example 1782-[[5-Chloro-4-[(2,5-difluorophenyl)-(4-fluorophenylthio)methyl]pyridin-2-yl]amino]ethanol

A 1,4-dioxane (1.5 ml) solution of2,5-dichloro-4-[(2,5-difluorophenyl)-(4-fluorophenylthio)methyl]pyridine(200 mg, 0.50 mmol) and 2-aminoethanol (300 μl) was stirred at 120° C.for 2 days under an argon atmosphere. After cooling to room temperature,the reaction mixture was concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (hexane:ethylacetate=1:1) to give the title compound (120 mg, 56%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 3.53(2H,m), 3.82(2H,m), 4.95(1H,br), 5.89(1H,s),6.74(1H,s), 6.90-7.00(4H,m), 7.16(1H,m), 7.31-7.36(2H,m), 7.99(1H,s).

MSm/z: 425(M⁺+H).

Example 1792-[[5-Chloro-4-[(2,5-difluorophenyl)-(4-fluorophenylsulfonyl)methyl]pyridin-2-yl]amino]ethanol

To a methanol (6 ml) solution of the2-[[5-chloro-4-[(2,5-difluorophenyl)-(4-fluorophenylthio)methyl]pyridin-2-yl]amino]ethanol(119 mg, 0.27 mmol) was added hexaammonium heptamolybdate tetrahydrate(30 mg), followed by further addition of 30% aqueous hydrogen peroxide(3 ml). The resulting mixture was stirred for 19 hours. After dilutionwith ethyl acetate (80 ml), the diluted mixture was washed with waterand brine, and concentrated under reduced pressure. The residue thusobtained was purified by silica gel chromatography (hexane:ethylacetate=1:1) and crystallized from ethanol to give the title compound(65 mg, 56%) as needle crystals.

¹H-NMR(400 MHz,CDCl₃)δ: 3.61(2H,m), 3.88(2H,d,J=4.8 Hz), 6.09(1H,s),6.90(1H,m), 7.04(1H,m), 7.10-7.18(2H,m), 7.42(1H,s), 7.49(1H,m),7.66-7.71(2H,m), 7.95(1H,s).

mp: 157 to 158° C.

Elemental Analysis for C₂₀H₁₆ClF₃N₂O₃S: Calculated: C, 52.58; H, 3.53;N, 6.13; S, 7.02; Cl, 7.76; F, 12.48. Found: C, 52.18; H, 3.51; N, 6.19;S, 7.10; Cl, 7.82; F, 12.38.

Example 1805-Chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]-2-[2-(pyridin-4-yl)ethylamino]pyridine

A dioxane (1.5 ml) solution of the2,5-dichloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine(220 mg, 0.528 mmol) obtained in Example 54 and 4-(2-aminoethyl)pyridine(400 μl) was heated at 120° C. for 3 days in a sealed tube. The reactionmixture was cooled to room temperature and then, concentrated underreduced pressure. Water was added to the residue thus obtained, followedby extraction with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous sodium sulfate, and filtered. The filtratewas concentrated under reduced pressure. The residue thus obtained wassubjected to silica gel column chromatography. The fraction obtainedfrom the methanol:methylene chloride=1:30 eluate was concentrated underreduced pressure to give the title compound (114 mg, 0.227 mmol, 43%) asa colorless oil.

¹H-NMR(400 MHz,CDCl₃)δ: 2.90(2H,t,J=7.1 Hz), 3.54-3.65(2H,m),4.70-4.81(1H,m), 5.96(1H,s), 6.64(1H,s), 6.90-7.03(2H,m),7.05-7.16(3H,m), 7.22(4H,s), 8.03(1H,s), 8.53(2H,d,J=6.1 Hz).

MSm/z: 501(M+).

Example 1815-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-2-[2-(pyridin-4-yl)ethylamino]pyridine

To a methanol (6 ml) solution of5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]-2-[2-(pyridin-4-yl)ethylamino]pyridine(110 mg, 0.219 mmol) were added 30% aqueous hydrogen peroxide (3 ml) andhexaammonium heptamolybdate tetrahydrate (34 mg) under ice cooling.After the reaction mixture was stirred at room temperature for 22 hours,methanol was distilled off under reduced pressure. To the residue thusobtained was added ethyl acetate. The resulting mixture was washedsequentially with saturated sodium bicarbonate, an aqueous solution ofsodium thiosulfate and brine, dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure. Theresidue thus obtained was subjected to silica gel column chromatography.The fraction obtained from the hexane:ethyl acetate=2:3 eluate wasconcentrated under reduced pressure to give the title compound (102 mg,0.191 mmol, 87%) as a pale yellowish white solid. The resulting solidwas washed with diisopropyl ether-hexane and collected by filtration toafford the title compound (87 mg) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 2.96(2H,t,J=7.1 Hz), 3.68(2H,q,J=6.8 Hz),4.72(1H,t,J=6.1 Hz), 6.12(1H,s), 6.89-6.96(1H,m), 6.98-7.08(1H,m),7.20(2H,d,J=5.9 Hz), 7.24(1H,s), 7.40-7.50(3H,m), 7.60(2H,d,J=8.6 Hz),8.03(1H,s), 8.56(2H,d,J=5.9 Hz).

mp: 148 to 150° C.

Elemental Analysis for C₂₅H₁₉N₃O₂Cl₂F₂S: Calculated: C, 56.19; H, 3.58;N, 7.86; Cl, 13.27; F, 7.11; S, 6.00. Found: C, 56.01; H, 3.57; N, 7.93;Cl, 13.27; F, 7.04; S, 6.16.

Example 1822-[2-[5-Chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-ylamino]ethoxy]ethanol

A dioxane (1.5 ml) solution of the2,5-dichloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine(210 mg, 0.504 mmol) obtained in Example 54 and 2-(2-aminoethoxy)ethanol(400 μl) was heated at 120° C. for 3 days in a sealed tube. The reactionmixture was cooled to room temperature and then, concentrated underreduced pressure. Water was added to the residue thus obtained, followedby extraction with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous sodium sulfate, and filtered. The filtratewas concentrated under reduced pressure. The residue thus obtained wassubjected to silica gel column chromatography. The fraction obtainedfrom the 30% methanol/methylene chloride eluate was concentrated underreduced pressure to give the title compound (85 mg, 0.175 mmol, 35%) asa colorless oil. ¹H-NMR(400 MHz,CDCl₃)δ: 2.11(1H,brs), 3.53(2H,q,J=5.3Hz), 3.61(2H,t,J=4.4 Hz), 3.70(2H,t,J=5.1 Hz), 3.72-3.80(2H,m),4.95(1H,t,J=5.6 Hz), 5.97(1H,s), 6.71(1H,s), 6.80-7.03(2H,s),7.08-7.17(1H,m), 7.18-7.30(4H,m), 8.03(1H,s).

MS(m/z): 484(M⁺).

Example 1832-[2-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-ylamino]ethoxy]ethanol

To a methanol (6 ml) solution of2-[2-[5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-ylamino]ethoxy]ethanol(80 mg, 0.155 mmol) were added 30% aqueous hydrogen peroxide (3 ml) andhexaammonium heptamolybdate tetrahydrate (32 mg) under ice cooling.After the resulting mixture was stirred at room temperature for 24hours, methanol was distilled off under reduced pressure. To the residuewas added ethyl acetate. The resulting mixture was washed sequentiallywith saturated sodium bicarbonate, an aqueous solution of sodiumthiosulfate and brine, dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated under reduced pressure. The residue thusobtained was subjected to silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate=2:3 eluate was concentrated underreduced pressure to give the title compound (70 mg, 0.135 mmol, 87%) asan amorphous substance. The resulting amorphous substance was solidifiedwith ether-hexane, followed by filtration to afford the title compound(55 mg) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 2.11(1H,brs), 3.55-3.63(2H,m), 3.66(2H,t,J=4.5Hz), 3.74(2H,t,J=5.1 Hz), 3.78-3.85(2H,m), 5.03-5.13(1H,m), 6.13(1H,s),6.89-6.97(1H,m), 6.98-7.08(1H,m), 7.30(1H,s), 7.45(2H,d,J=8.5 Hz),7.48-7.56(1H,m), 7.62(2H,d,J=8.5 Hz), 8.00(1H,s). mp: 113 to 115° C.

Elemental Analysis for C₂₂H₂₀N₂O₄Cl₂F₂S: Calculated: C, 51.07; H, 3.90;N, 5.41; Cl, 13.70; F, 7.34; S, 6.20. Found: C, 50.81; H, 3.83; N, 5.49;Cl, 13.64; F, 7.46; S, 6.34.

Example 1845-Chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]-2-[(3-methoxypropyl)amino]pyridine

A dioxane (1.5 ml) solution of the2,5-dichloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine(216 mg, 0.518 mmol) obtained in Example 54 and 3-methoxypropylamine(200 μl) was heated at 120° C. for 3 days in a sealed tube. The reactionmixture was cooled to room temperature, and then concentrated underreduced pressure. The residue thus obtained was subjected to silica gelcolumn chromatography. The fraction obtained from the hexane:ethylacetate (=3:1) eluate was concentrated under reduced pressure to give apale yellow oil (101 mg).

To a methanol (6 ml) solution of the resulting pale yellow oil (101 mg)were added 30% aqueous hydrogen peroxide (3 ml) and hexaammoniumheptamolybdate tetrahydrate (41 mg) under ice cooling. After thereaction mixture was stirred at room temperature for 16 hours, methanolwas distilled off under reduced pressure. To the residue thus obtainedwas added ethyl acetate. The resulting mixture was washed sequentiallywith saturated sodium bicarbonate, an aqueous solution of sodiumthiosulfate and brine, dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated under reduced pressure. The residue thusobtained was subjected to silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate=3:1 eluate was concentrated underreduced pressure to give the title compound (90 mg, 0.180 mmol, 35%) asa white solid. The solid thus obtained was washed with ether-hexane andcollected by filtration to afford the title compound (64 mg) as a whitepowder.

¹H-NMR(400 MHz,CDCl₃)δ: 1.87-1.98(2H,m), 3.39(3H,s), 3.46(2H,q,J=6.1Hz), 3.55(2H,t,J=5.8 Hz), 5.09(1H,brt,J=5.3 Hz), 6.13(1H,s),6.88-6.96(1H,m), 6.98-7.08(1H,m), 7.20(1H,s), 7.43(2H,d,J=8.7 Hz),7.50-7.57(1H,m), 7.62(2H,d,J=8.7 Hz), 7.98(1H,s).

mp: 146 to 148° C.

Elemental Analysis for C₂₂H₂₀N₂O₃Cl₂F₂S: Calculated: C, 52.70; H, 4.02;N, 5.59; Cl, 14.14; F, 7.58; S, 6.40. Found: C, 52.72; H, 3.95; N, 5.78;Cl, 14.14; F, 7.75; S, 6.54.

Example 1855-Chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]-2-(3,4-dimethoxybenzylamino)pyridine

A dioxane (1.5 ml) solution of the2,5-dichloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine(218 mg, 0.523 mmol) obtained in Example 54 and 3,4-dimethoxybenzylamine(400 μl) was heated at 120° C. for 3 days in a sealed tube. The reactionmixture was cooled to room temperature and then, concentrated underreduced pressure. The residue thus obtained was subjected to silica gelcolumn chromatography. The fraction obtained from the hexane:ethylacetate=4:1 eluate was concentrated under reduced pressure to give thetitle compound (140 mg, 0.256 mmol, 49%) as an amorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 3.86(3H,s), 3.88(3H,s), 4.42(2H,d,J=5.6 Hz),4.99(1H,t,J=5.6 Hz), 5.95(1H,s), 6.68(1H,s), 6.80-7.02(6H,m),7.12-7.21(4H,m), 8.05(1H,s).

MSm/z: 547(M⁺+H).

Example 1865-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-2-(3,4-dimethoxybenzylamino)pyridine

To a methanol (6 ml) solution of5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]-2-(3,4-dimethoxybenzylamino)pyridine(131 mg, 0.239 mmol) were added 30% aqueous hydrogen peroxide (3 ml) andhexaammonium heptamolybdate tetrahydrate (31 mg) under ice cooling.After the reaction mixture was stirred at room temperature for 16 hours,methanol was distilled off under reduced pressure. Ethyl acetate wasadded to the residue thus obtained. The resulting mixture was washedsequentially with saturated sodium bicarbonate, an aqueous solution ofsodium thiosulfate and brine, dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure. Theresidue thus obtained was subjected to flash silica gel columnchromatography. The fraction obtained from the 35% ethyl acetate/hexaneeluate was concentrated under reduced pressure to give the titlecompound (75 mg, 0.129 mmol, 54%) as a white solid. The resulting whitesolid was washed with ether-hexane, and filtered to give the titlecompound as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 3.89(6H,s), 4.48-4.51(2H,m), 5.08-5.15(1H,m),6.12(1H,s), 6.85-7.05(5H,m), 7.24(1H,s), 7.28-7.35(1H,m),7.40(2H,d,J=8.5 Hz), 7.55(2H,d,J=8.5 Hz), 8.01(1H,s).

mp: 204 to 206° C.

Elemental Analysis for C₂₇H₂₂N₂O₄Cl₂F₂S: Calculated: C, 55.97; H, 3.83;N, 4.83; Cl, 12.24; F, 6.56; S, 5.53. Found: C, 56.05; H, 3.82; N, 4.87;Cl, 12.30; F, 6.60; S, 5.73.

Example 1875-Chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]-2-[(pyridin-4-ylmethyl)amino]pyridine

A dioxane (1.5 ml) solution of the2,5-dichloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine(229 mg, 0.550 mmol) obtained in Example 54 and 4-aminomethylpyridine(200 μl) was heated at 120° C. for 3 days in a sealed tube. The reactionmixture was cooled to room temperature and then concentrated underreduced pressure. The residue thus obtained was subjected to silica gelcolumn chromatography. The fraction obtained from the hexane:ethylacetate=1:3 eluate was concentrated under reduced pressure to give thetitle compound (37 mg, 0.076 mmol, 14%) as an amorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 4.55(2H,d,J=6.1 Hz), 5.06(1H,t,J=6.0 Hz),5.94(1H,s), 6.61(1H,s), 6.90-7.09(3H,m), 7.13-7.30(6H,m), 8.05(1H,s),8.55(2H,d,J=6.1 Hz).

MSm/z: 488(M⁺+H).

Example 1885-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-2-[(pyridin-4-ylmethyl)amino]pyridine

To a methanol (2 ml) solution of5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]-2-[(pyridin-4-ylmethyl)amino]pyridine(35 mg, 0.072 mmol) were added 30% aqueous hydrogen peroxide (3 ml) andhexaammonium heptamolybdate tetrahydrate (23 mg) under ice cooling Afterthe reaction mixture was stirred at room temperature for 22 hours,methanol was distilled off under reduced pressure. Ethyl acetate wasadded the residue. The resulting mixture was washed sequentially withsaturated sodium bicarbonate, an aqueous solution of sodium thiosulfateand brine, dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure. The residue thusobtained was subjected to silica gel column chromatography. The fractionobtained from the methanol:methylene chloride=1:30 eluate wasconcentrated under reduced pressure to give a pale yellow solid. Theresulting pale yellow solid was washed with ether-hexane and filtered togive the title compound (16 mg, 0.031 mmol, 43%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 4.63(2H,dd,J=6.1,2.9 Hz), 5.20(1H,t,J=6.4 Hz),6.11(1H,s), 6.87-6.95(1H,m), 6.99-7.08(1H,m), 7.25(1H,s),7.30(2H,d,J=6.0 Hz), 7.35-7.40(1H,m), 7.42(2H,d,J=8.9 Hz),7.56(2H,d,J=8.9 Hz), 8.02(1H,s), 8.59(2H,d,J=6.0 Hz).

mp: 141 to 142° C.

FAB-MS: 520.0465 (Calcd for C₂₄H₁₈O₂N₃Cl₂F₂S: 520.0461).

Example 189N-[3-[[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]propyl]methanesulfonamide

To a methylene chloride solution (5.0 ml) of theN-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]propane-1,3-diaminedihydrochloride (60 mg, 0.107 mmol) obtained in Example 173 were addedtriethylamine (70 μl, 0.05 mmol) and methanesulfonyl chloride (10 μl,0.13 mmol). The resulting mixture was stirred for 20 minutes. To thereaction mixture was added ether (50 ml). The resulting mixture waswashed with water and brine, dried and concentrated under reducedpressure. The residue thus obtained was purified by silica gelchromatography (hexane:ethyl acetate=2:1) to give the title compound (60mg, 99%). The resulting compound was crystallized in ethanol to afford awhite solid (46 mg).

¹H-NMR(40 MHz,CDCl₃)δ: 1.86(2H,quint,J=6.0 Hz), 2.95(3H,s),3.21(2H,q,J=6.0 Hz), 3.55(2H,q,J=6.0 Hz), 4.99(1H,br), 5.65(1H,br),6.11(1H,s), 6.91(1H,m), 7.03(1H,m), 7.29(1H,s), 7.44(2H,d,J=8.8 Hz),7.49(1H,m), 7.60(2H,d,J=8.8 Hz), 8.00(1H,s).

mp: 138 to 139° C.

Elemental Analysis for C₂₂H₂₁Cl₂F₂N₃O₄S₂: Calculated: C, 46.81; H, 3.75;N, 7.44; S, 11.36; F, 6.73; Cl, 12.56; Found: C, 46.81; H, 3.72; N,7.43; S, 11.39; F, 6.80; Cl, 12.41.

Example 1901-[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]tetrahydropyrimidin-2-one

To a methylene chloride solution (5.0 ml) of theN-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]propane-1,3-diaminedihydrochloride (51 mg, 0.091 mmol) obtained in Example 173 were addedtriethylamine (51 μl, 0.36 mmol) and 1,1′-carbonyldiimidazole (16.2 mg,0.10 mmol). The resulting mixture was stirred for 17 hours. To thereaction mixture was added ethyl acetate (80 ml). The resulting mixturewas washed with water and brine, dried and concentrated under reducedpressure. The residue thus obtained was dissolved in dimethylformamide(1.0 ml). To the resulting solution was added potassium carbonate (27.2mg, 0.2 mol), followed by stirring under heat at 50° C. for 24 hours.After cooling to room temperature, water was added to the reactionmixture. The resulting mixture was diluted with ethyl acetate (60 ml).The organic layer obtained by separation was washed with brine, driedand concentrated under reduced pressure. The residue thus obtained waspurified by silica gel chromatography (hexane:ethyl acetate=1:2) to givethe title compound (15 mg, 99%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 2.12(2H,m), 3.46(2H,m), 3.99(2H,m), 5.22(1H,br),6.26(1H,s), 6.96(1H,m), 7.03(1H,m), 7.43(2H,d,J=8.8 Hz), 7.68(1H,m),7.76(2H,d,J=8.8 Hz), 8.23(1H,s), 8.93(1H,s).

MSm/z: 512 (M⁺+H).

mp: >230° C.

Example 191 t-Butyl2-[[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]ethylcarbamate

A 1,4-dioxane (6.0 ml) solution of the2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine(610 mg, 1.46 mmol) obtained in Example 54 andt-butyl(2-aminoethyl)carbamate (700 mg, 4.38 mmol) was stirred at 120°C. for 4 days under an argon atmosphere. After cooling to roomtemperature, the reaction mixture was concentrated under reducedpressure. The residue was purified by silica gel chromatography(hexane:ethyl acetate=4:1) to give the title compound (176 mg, 22%) asan oil.

¹H-NMR(400 MHz,CDCl₃)δ: 1.43(9H,s), 3.36(2H,m), 3.42(2H,m), 5.01(1H,br),5.12(1H,br), 5.95(1H,s), 6.90-7.04(2H,m), 7.13(1H,m), 7.21(2H,d,J=8.4Hz), 7.23(2H,d,J=8.4 Hz), 8.00(1H,s).

MSm/z: 540(M⁺+H).

Example 192 t-Butyl2-[[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]ethylcarbamate

To a methanol (6 ml) solution of t-butyl2-[[5-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]ethylcarbamate(176 mg, 0.32 mmol) was added hexaammonium heptamolybdate tetrahydrate(30 mg), followed by further addition of 30% aqueous hydrogen peroxide(3 ml). The resulting mixture was stirred for 20 hours. After thereaction mixture was diluted with ethyl acetate (80 ml), the dilutedmixture was washed with water and brine, and concentrated under reducedpressure. The residue thus obtained was purified by silica gelchromatography (hexane:ethyl acetate=3:1) to give the title compound(148 mg, 81%) as an oil.

¹H-NMR(400 MHz,CDCl₃)δ: 1.45(9H,s), 3.39(2H,m), 3.49(2H,m), 5.03(1H,br),5.29(1H,br), 6.12(1H,s), 6.91(1H,m), 7.03(1H,m), 7.24(1H,s),7.43(2H,d,J=8.8 Hz), 7.52(1H,m), 7.61(2H,d,J=8.8 Hz), 7.98(1H,s).

MSm/z: 572(M⁺+H).

Example 193N-[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]ethane-1,2-diaminedihydrochloride

To t-butyl2-[[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]ethylcarbamate(146 mg, 0.25 mmol) was added a 20% hydrochloric acid-methanol solution(1 ml). The resulting mixture was stirred for 1 hour. The residueobtained by concentrating the reaction mixture under reduced pressurewas crystallized from ethanol to give the title compound (106 mg, 76%).

¹H-NMR(400 MHz,DMSO-d₆)δ: 2.99(2H,m), 3.51(2H,m), 6.17(1H,s),7.28(1H,m), 7.38(1H,m), 7.39(1H,s), 7.52(1H,m), 7.69(2H,d,J=8.8 Hz),7.75(2H,d,J=8.8 Hz), 8.04(1H,s).

mp: 163 to 166° C.

Elemental Analysis for C₂₀H₁₇Cl₂F₂N₃O₂S.2HCl.0.5H₂O: Calculated: C,43.34; H, 3.64; N, 7.58; S, 5.78; Cl, 25.59; F, 6.86. Found: C, 43.32;H, 3.55; N, 7.67; S, 5.83; Cl, 25.84; F, 6.87.

Example 1943-[5-Chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-ylamino]-2,2-dimethylpropan-1-ol

A dioxane (1.5 ml) solution of the2,5-dichloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine(191 mg, 0.458 mmol) obtained in Example 54 and3-amino-2,2-dimethylpropan-1-ol (515 mg, 5.00 mmol) was heated at 120°C. for 3 days in a sealed tube. The reaction mixture was cooled to roomtemperature and then, concentrated under reduced pressure. Ethyl acetatewas added to the residue. The resulting mixture was washed sequentiallywith water and brine, dried over anhydrous sodium sulfate, and filtered.The filtrate was concentrated under reduced pressure. The residue thusobtained was subjected to silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate=3:1 eluate was concentrated underreduced pressure to give the title compound (199 mg, 0.412 mmol, 90%) asan amorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 0.91(6H,s), 3.12-3.28(4H,m), 4.73(1H,t,J=6.4Hz), 4.87(1H,brs), 5.92(1H,s), 6.62(1H,s), 6.92-7.07(2H,m),7.16-7.32(5H,m), 7.96(1H,m).

MSm/z: 483(M⁺+H).

Example 1953-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-ylamino]-2,2-dimethylpropan-1-ol

To a methanol (6 ml) solution of3-[5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-ylamino]-2,2-dimethylpropan-1-ol(188 mg, 0.389 mmol) were added 30% aqueous hydrogen peroxide (3 ml) andhexaammonium heptamolybdate tetrahydrate (35 mg) under ice cooling.After the resulting mixture was stirred at room temperature for 13hours, methanol was distilled off under reduced pressure. To the residuethus obtained was added ethyl acetate. The resulting mixture was washedsequentially with saturated sodium bicarbonate, an aqueous solution ofsodium thiosulfate and brine, dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure. Theresidue thus obtained was subjected to silica gel column chromatography.The fraction obtained from the hexane:ethyl acetate=3:1 eluate wasconcentrated under reduced pressure to give a white solid. The resultingwhite solid was solidified with ether-hexane, washed and collected byfiltration to afford the title compound (156 mg, 0.303 mmol, 78%) as awhite powder.

¹H-NMR(400 MHz,CDCl₃)δ: 0.94(3H,s), 0.95(3H,s), 3.20(2H,d,J=6.6 Hz),3.27(2H,d,J=7.1 Hz), 4.68(1H,brs), 4.94(1H,t,J=6.9 Hz), 6.09(1H,s),6.86-6.95(1H,m), 7.00-7.09(1H,m), 7.29(1H,s), 7.40-7.52(3H,m),7.60(2H,d,J=8.6 Hz), 7.94(1H,s).

mp: 176 to 178° C.

Elemental Analysis for C₂₃H₂₂N₂O₃Cl₂F₂S: Calculated: C, 53.60; H, 4.30;N, 5.44; Cl, 13.76; F, 7.37; S, 6.22. Found: C, 53.50; H, 4.26; N, 5.44;Cl, 13.78; F, 7.31; S, 6.30.

Example 196[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine

To an acetonitrile (4 ml)/water (1 ml) mixed solution of the5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-2-(3,4-dimethoxybenzylamino)pyridine(43 mg, 0.074 mmol) obtained in Example 186 was added cerium (IV)diammonium nitrate (100 mg) under ice cooling. The resulting mixture wasstirred for 1.5 hours. To the reaction mixture was added saturatedsodium bicarbonate, followed by extraction with methylene chloride. Theorganic layer was dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure. The residue thusobtained was purified by silica gel thin-layer chromatography(hexane:ethyl acetate=3:1) to give the title compound (12 mg, 0.028mmol, 38%) as a pale yellowish white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 4.65(2H,brs), 6.13(1H,s), 6.89-6.98(1H,m),7.00-7.09(1H,m), 7.33(1H,s), 7.44(2H,d,J=8.8 Hz), 7.49-7.57(1H,m),7.62(2H,d,J=8.8 Hz), 7.99(1H,s).

mp: 147 to 150° C.

MSm/z: 429(M⁺+H).

Elemental Analysis for C₁₈H₁₂N₂O₂Cl₂F₂S: Calculated: C, 50.36; H, 2.82;N, 6.53; Cl, 16.52; F, 8.85; S, 7.47. Found: C, 50.46; H, 2.68; N, 6.63;Cl, 16.42; F, 9.00; S, 7.66.

Example 197N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]methanesulfonamide

To a pyridine (2 ml) solution of the[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine(106 mg, 0.247 mmol) obtained in Example 196 was added methanesulfonylchloride (29 μl, 0.370 mmol) under ice cooling. The resulting mixturewas stirred at room temperature for 3 days and concentrated underreduced pressure. To the residue thus obtained was added ethyl acetate.The resulting mixture was washed sequentially with a saturated aqueoussolution of sodium bicarbonate, water and brine, dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated underreduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=3:1 eluate was concentrated under reduced pressureto give the title compound (58 mg, 0.114 mmol, 46%) as a white solid.The resulting white solid was washed with hexane-ether and collected byfiltration to give the title compound (28 mg) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 3.35(3H,s), 6.19(1H,s), 6.90-6.99(1H,m),7.01-7.10(1H,m), 7.42-7.53(3H,m), 7.60-7.70(3H,m), 7.97(1H,s),8.32(1H,s).

mp: 220 to 222° C.

MSm/z: 507(M⁺+H).

FAB-MS: 506.9824 (cald for C₁₉H₁₅O₄N₂Cl₂F₂S₂: 506.9818).

Elemental Analysis for C₁₉H₁₄N₂O₄Cl₂F₂S₂: Calculated: C, 44.98; H, 2.78;N, 5.52; Cl, 13.98; F, 7.49; S, 12.64. Found: C, 45.35; H, 2.85; N,5.63; Cl, 13.49; F, 7.34; S, 12.69.

Referential Example 35 5-Fluoropyridine-2-carbonitrile

To hydrogen fluoride-pyridine (100 ml) was added 5-amino-2-cyanopyridine(24.5 g, 0.206 mol) under ice cooling. The resulting mixture was stirredfor 10 minutes. To the reaction mixture was added sodium nitrite (15.6g, 0.226 mol). The resulting mixture was stirred at room temperature for10 minutes, and then stirred at 50° C. for 2 hours. To the reactionmixture was added a 20% aqueous solution of sodium hydroxide. Theresulting mixture was extracted with diethyl ether. The organic layerthus obtained was dried over sodium sulfate, and concentrated underreduced pressure. The residue thus obtained was subjected to silica gelcolumn chromatography. The fraction obtained from the hexane:ethylacetate=3:1 eluate was concentrated under reduced pressure to give thetitle compound (16.0 g, 0.131 mmol, 64%) as colorless needle crystals.

¹H-NMR(400 MHz,CDCl₃)δ: 7.57(1H,ddd,J=8.6,8.6,3.1 Hz),7.77(1H,dd,J=8.6,4.4 Hz), 8.60(1H,d,J=3.1 Hz).

IR(ATR)cm⁻¹: 3095, 2237, 1577, 1467, 1409, 1375, 1272, 1240, 1197, 1120,1010.

MSm/z: 122(M⁺).

EI-MS: 122.0293 (Calcd for C₆H₃FN₂: 122.0280).

Referential Example 36 2-(1,3-dioxolan-2-yl)-5-fluoropyridine

Diisobutylaluminum hydride (a 1.01M hexane solution, 58 ml, 58.9 mmol)was added dropwise to a dichloromethane (150 ml) solution of5-fluoropyridine-2-carbonitrile (6.54 g, 53.8 mmol) at −75° C. under anargon atmosphere. The reaction mixture was stirred for 3 hours. At thesame temperature, hydrochloric acid (80 ml) (concentrated hydrochloricacid:water=1:3) was added, followed by heating to room temperature. Fromthe reaction mixture, a dichloromethane layer was separated. To thewater layer was then added sodium bicarbonate. The resulting mixture wasextracted with diethyl ether. The organic layer thus obtained was driedover magnesium sulfate, and concentrated under reduced pressure. Thedichloromethane layer obtained previously was washed with water, driedover magnesium sulfate, and concentrated under reduced pressure.

To a benzene (150 ml) solution of the combined residues were addedp-toluenesulfonic acid monohydrate (1.02 g, 5.36 mmol) and ethyleneglycol (30 ml, 0.536 mol). Under heating under reflux, the resultingmixture was stirred for 2 hours. After cooling, a saturated aqueoussolution of sodium bicarbonate was added and the resulting mixture wasextracted with diethyl ether. The extract was washed with brine. Theorganic layer thus obtained was dried over magnesium sulfate, andconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate=4:1 eluate was concentrated underreduced pressure to give the title compound (3.33 g, 19.7 mmol, 37%) asa reddish brown oil.

¹H-NMR(400 MHz,CDCl₃)δ: 4.02-4.21(4H,m), 5.85(1H,s),7.45(1H,ddd,J=8.3,8.3,2.9 Hz), 7.57(1H,dd,J=8.3,4.5 Hz), 8.48(1H,d,J=2.9Hz).

MSm/z: 170(M⁺+H)

Referential Example 374-[(2,5-Difluorophenyl)hydroxymethyl]-2-(1,3-dioxolan-2-yl)-5-fluoropyridine

Lithium diisopropylamide (a 1.8M heptane solution, 12 ml, 21.5 mmol) wasadded to a tetrahydrofuran (100 ml) solution of2-(1,3-dioxolan-2-yl)-5-fluoropyridine (690 mg, 4.08 mmol) at −75° C.under an argon atmosphere. The resulting mixture was stirred for 2hours. To the reaction mixture was added dropwise2,5-difluorobenzaldehyde (2.1 ml, 19.5 mmol), followed by stirring for2.5 hours. To the reaction mixture were added water and a saturatedaqueous solution of sodium bicarbonate. The resulting mixture wasextracted with diethyl ether. The extract was washed with brine. Theorganic layer thus obtained was dried over magnesium sulfate andconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate (=3:1) eluate was concentratedunder reduced pressure to give the title compound (2.53 g, 8.03 mmol,73%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 2.65(1H,d,J=4.6 Hz), 4.05-4.21(4H,m),5.84(1H,s), 6.35(1H,d,J=4.6 Hz), 6.96-7.05(2H,m), 7.09-7.26(1H,m),7.76(1H,d,J=5.9 Hz), 8.40(1H,d,J=1.5 Hz).

MSm/z: 312(M⁺+H).

Example 1984-[(4-Chlorophenylthio)(2,5-difluorophenyl)methyl]-2-(1,3-dioxolan-2-yl)-5-fluoropyridine

Under an argon atmosphere, triethylamine (1.7 ml, 12.0 mmol) andmethanesulfonyl chloride (850 μl, 10.4 mmol) were added to adichloromethane solution (30 ml) of4-[(2,5-difluorophenyl)hydroxymethyl]-2-(1,3-dioxolan-2-yl)-5-fluoropyridine(2.5 g, 8.03 mmol) under ice cooling. The resulting mixture was stirredat room temperature for 2 hours. A saturated aqueous solution of sodiumbicarbonate was added to the reaction mixture, followed by extractionwith diethyl ether. The extract was washed with brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure.

To a dimethylformamide (20 ml) solution of the residue were added4-chlorobenzenethiol (1.39 g, 9.64 mmol) and potassium carbonate (1.66g, 12.0 mmol). The resulting mixture was stirred at 50° C. for 3 hours.After cooling to room temperature, the reaction mixture was diluted withdiethyl ether. The diluted solution was washed sequentially with waterand brine. The organic layer thus obtained was dried over sodiumsulfate, and concentrated under reduced pressure. The residue thusobtained was subjected to flash silica gel column chromatography. Thefraction obtained from the hexane:ethyl acetate (=4:1) eluate wasconcentrated under reduced pressure to give the title compound (2.86 g,5.85 mmol, 81%) as a yellow oil.

¹H-NMR(40.0 MHz,CDCl₃)δ: 4.06-4.18(4H,m), 5.82(1H,s), 5.94(1H,s),6.96-7.03(2H,m), 7.20-7.28(5H,m), 7.71(1H,d,J=5.9 Hz), 8.38(1H,d,J=1.2Hz).

MSm/z: 438 (M⁺+H).

Example 1994-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-2-(1,3-dioxolan-2-yl)-5-fluoropyridine

To a methanol (50 ml) solution of4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]-2-(1,3-dioxolan-2-yl)-5-fluoropyridine(2.80 g, 6.39 mmol) were added hexaammonium heptamolybdate tetrahydrate(200 mg) and 30% aqueous hydrogen peroxide (30 ml). The resultingmixture was stirred for 3 hours. Water was added do the reactionmixture. The solid thus precipitated was collected by filtration andthen, washed with water. The resulting solid was dissolved in ethylacetate. The resulting solution was washed with water and brine. Theorganic layer was concentrated under reduced pressure. The residue thusobtained was subjected to flash silica gel column chromatography. Thefraction obtained from the hexane:ethyl acetate (=3:1) eluate wasconcentrated under reduced pressure to give the title compound (1.39 g,2.96 mmol, 46%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 4.08-4.28(4H,m), 4.08-4.28(4H,m), 5.88(1H,s),6.10(1H,s), 6.94-7.00(1H,m), 7.03-7.10(1H,m), 7.43(2H,d,J=8.3 Hz),7.62(2H,d,J=8.3 Hz), 7.66-7.70(1H,m), 8.17(1H,d,J=5.9 Hz), 8.41(1H,s).

MSm/z: 470(M⁺+H)

Example 200[4-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropyridin-2-yl]carbaldehyde

To a 1,4-dioxane (40 ml) solution of4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-2-(1,3-dioxolan-2-yl)-5-fluoropyridine(2.60 g, 5.53 mmol) was added concentrated hydrochloric acid (20 ml).The resulting mixture was stirred at room temperature for 5 hours. Thesolvent was concentrated under reduced pressure. To the residue wasadded ethyl acetate. The resulting mixture was washed sequentially withwater, a saturated aqueous solution of sodium bicarbonate and brine. Theorganic layer thus obtained was dried over magnesium sulfate, andconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate (=3:1) eluate was concentratedunder reduced pressure to give the title compound (1.86 g, 4.37 mmol,79%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 6.13(1H,s), 6.93-6.99(1H,m), 7.05-7.10(1H,m),7.45(2H, d,J=7.8 Hz), 7.65(2H,d,J=7.8 Hz), 7.70-7.75(1H,m), 8.59(1H,s),8.60(1H,s), 10.06(1H,s).

MSm/z: 426(M⁺+H).

Example 2014-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropicolinicacid

To a formic acid (10 ml) solution of[4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropyridin-2-yl]carbaldehyde(700 mg, 1.64 mmol) were added 30% aqueous hydrogen peroxide (562 μl,4.93 mmol). The resulting mixture was stirred at room temperature for2.5 hours. Water was added to the reaction mixture. The solid thusprecipitated was collected by filtration and washed with water. Theresulting solid was dissolved in ethyl acetate. The resulting solutionwas washed sequentially with a saturated aqueous solution of ammoniumchloride, water and brine. The organic layer thus obtained was driedover magnesium sulfate, and concentrated under reduced pressure. Theresidue thus obtained was recrystallized from ethanol to give the titlecompound (656 mg, 1.48 mmol, 91%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 6.14(1H,s), 6.93-7.00(1H,m), 7.05-7.11(1H,m),7.46(2H,d,J=8.6 Hz), 7.67(2H,d,J=8.6 Hz), 7.75-7.79(1H,m), 8.47(1H,s),8.85(1H,d,J=5.6 Hz).

IR(ATR)cm⁻¹: 3288, 2942, 1751, 1722, 1693, 1608, 1575, 1492, 1398, 1326,1290, 1241, 1182, 1147, 1089, 1043, 1014)

mp: 208 to 209° C.

MSm/z: 442(M⁺+H).

Elemental Analysis for C₁₉H₁₁ClF₃NO₄S.0.75H₂O: Calculated: C, 50.12; H,2.77; Cl, 7.79; F, 12.52; N, 3.08; S, 7.04. Found: C, 50.49; H, 2.97;Cl, 7.53; F, 12.02; N, 3.11, S, 6.89.

Example 202t-Butyl[4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropyridin-2-yl]carbamate

Under an argon atmosphere, diphenylphosphoryl azide (162 μl, 0.762 mmol)and triethylamine (151 μl, 1.09 mmol) were added to a solution of4-[-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropicolinicacid (240 mg, 0.543 mmol) in a mixture of t-butanol (2 ml) and toluene(5 ml). The reaction mixture was heated under reflux for 15 hours. Aftercooling, ethyl acetate was added to the reaction mixture. The resultingmixture was washed sequentially with a saturated aqueous solution ofsodium bicarbonate and brine. The organic layer thus obtained was driedover magnesium sulfate, and concentrated under reduced pressure. Theresidue thus obtained was subjected to flash silica gel columnchromatography. The fraction obtained from the hexane:ethyl acetate(=4:1) eluate was concentrated under reduced pressure to give the titlecompound (181 mg, 0.353 mmol, 65%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 1.57(9H,s), 6.07(1H,s), 6.93-6.99(1H,m),7.02-7.08(1H,m), 7.43(2H,d,J=8.6 Hz), 7.49(1H,brs), 7.70(2H,d,J=8.6 Hz),7.71-7.75(1H,m), 8.04(1H,s), 8.65(1H,d,J=4.9 Hz).

MSm/z: 442(M⁺-tBu+2H).

Example 203[4-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropyridin-2-yl]amine

To an ethanol (5 ml) solution oft-butyl[4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropyridin-2-yl]carbamate(170 mg, 0.331 mmol) was added concentrated hydrochloric acid (5 ml).The resulting mixture was stirred at room temperature for 2 hours. Thereaction mixture was concentrated under reduced pressure. To the residuethus obtained was added a saturated aqueous solution of sodiumbicarbonate, followed by extraction with ethyl acetate. The organiclayer was washed with brine, dried over magnesium sulfate, andconcentrated under reduced pressure. The residue thus obtained wasrecrystallized from hexane:ethyl acetate to give the title compound (110mg, 0.266 mmol, 81%) as a pale violet powder.

¹H-NMR(400 MHz,CDCl₃)δ: 4.51(2H,s), 5.99(1H,s), 6.92-6.97(1H,m),7.02-7.08(1H,m), 7.16(1H,d,J=4.6 Hz), 7.44(2H,d,J=8.6 Hz),7.61-7.65(1H,m), 7.63(2H,d,J=8.6 Hz), 7.86(1H,s).

IR(ATR)cm⁻¹: 3645, 3174, 1631, 583, 1565, 1496, 1427, 1396, 1330, 1278,1236, 1178, 1151, 1085, 1014.

mp: 181 to 183° C.

MSm/z: 413(M⁺+H).

Elemental Analysis for C₁₈H₁₂ClF₃N₂O₂S: Calculated: C, 52.37; H, 2.93;Cl, 8.59; F, 13.81; N, 6.79; S, 7.77. Found: C, 52.09; H, 2.88; Cl,8.57; F, 13.54; N, 6.90; S, 7.81.

Example 204N-[4-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropyridin-2-yl]methanesulfonamide

Under ice cooling, methanesulfonyl chloride (12 μl, 0.157 mmol) wasadded to a methylene chloride (5 ml) solution of[4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropyridin-2-yl]amine(54 mg, 0.131 mmol) and pyridine (16 μl, 0.197 mmol). The resultingmixture was stirred at room temperature for 7 hours, followed by theaddition of pyridine (16 μl, 0.197 mmol) and methanesulfonyl chloride(12 μl, 0.157 mmol). After the reaction mixture was stirred at roomtemperature for 17 hours, pyridine (16 μl, 0.197 mmol) andmethanesulfonyl chloride (12 μl, 0.157 mmol) were added thereto. Theresulting mixture was stirred at room temperature for 2 hours and then,pyridine (16 μl, 0.197 mmol) and methanesulfonyl chloride (12 μl, 0.157mmol) were added thereto. After the resulting mixture was stirred atroom temperature for 21 hours, pyridine (16 μl, 0.197 mmol) andmethanesulfonyl chloride (12 μl, 0.157 mmol) were added thereto. Theresulting mixture was stirred at room temperature for 2 hour and then,concentrated under reduced pressure. To the residue thus obtained wasadded ethyl acetate. The resulting mixture was washed with a saturatedaqueous solution of sodium bicarbonate, dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure. The residue thus obtained was subjected to flash silica gelcolumn chromatography. The fraction obtained from the hexane:ethylacetate (=2:1) eluate was concentrated under reduced pressure to givethe title compound (54 mg, 0.110 mmol, 84%) as a white solid. Theresulting white solid was washed with hexane-ether, and collected byfiltration to afford the title compound as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 3.30(3H,s), 6.06(1H,s), 6.90-6.99(1H,m),7.02-7.10(1H,m), 7.46(2H,d,8.8 Hz), 7.58-7.69(3H,m), 7.83-7.91(2H,m),8.21(1H,s).

mp: 217 to 219° C.

MSm/z: 490(M⁺).

EI-MS: 490.0008 (calculated as C₁₉H₁₄O₄N₂ClF₃S₂: 490.0036).

Elemental Analysis for C₁₉H₁₄N₂O₄ClF₃S₂: Calculated: C, 46.49; H, 2.87;N, 5.71; Cl, 7.22; F, 11.61; S, 13.06. Found: C, 46.90; H, 2.95; N,5.78; Cl, 7.33; F, 11.56; S, 13.04.

Referential Example 38 (4-Bromo-5-methylpyridin-2-yl)methanol

Under an argon atmosphere, trifluoroacetic anhydride (20.6 ml, 0.146mol) was added to a dichloromethane solution (100 ml) solution of4-bromo-2,5-dimethylpyridine 1-oxide (9.8 g, 48.5 mmol) under icecooling. The resulting mixture was stirred for 20 minutes and then,stirred at room temprerature for 7.5 hours. The reaction mixture wasconcentrated under reduced pressure. To a dichloromethane solution (50ml) of the residue was added a saturated aqueous solution (100 ml) ofsodium bicarbonate. The resulting mixture was stirred for 14 hours. Thereaction mixture was extracted with dichloromethane. The extract wasdried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue thus obtained was subjected to silica gel columnchromatography. The fraction obtained from the hexane:ethyl acetate(=1:1) eluate was concentrated under reduced pressure to give the titlecompound (8.17 g, 40.4 mmol, 83%) as a yellow powder.

¹H-NMR(400 MHz,CDCl₃)δ: 2.38(3H,s), 3.42(1H,s), 4.71(2H,s), 7.48(1H,s),8.35(1H,s).

MSm/z: 202(M⁺+H).

Referential Example 394-Bromo-2-[(t-butyldimethylsilyloxy)methyl]-5-methylpyridine

Under a nitrogen atmosphere, imidazole (2.95 g, 43.3 mmol),4-dimethylaminopyridine (481 mg, 3.94 mmol) andt-butylchlorodimethylsilane (6.53 g, 43.3 mmol) were added to adichloromethane solution (100 ml) of(4-bromo-5-methylpyridin-2-yl)methanol (7.96 g, 39.4 mmol) under icecooling. The resulting mixture was stirred at room temperature for 1hour. Water was added to the reaction mixture, followed by extractionwith dichloromethane. The extract was dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue thusobtained was subjected to silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate=4:1 eluate was concentrated underreduced pressure to give the title compound (12.4 g, 39.4 mmol, quant.)as a pale yellow oil.

¹H-NMR(400 MHz,CDCl₃)δ: 0.12(6H,s), 0.96(9H,s), 2.36(3H,s), 4.78(2H,s),7.67(1H,s), 8.29(1H,s).

MSm/z: 316(M⁺+H).

Referential Example 402-[(t-Butyldimethylsilyloxy)methyl]-4-[(2,5-difluorophenyl)hydroxymethyl]-5-methylpyridine

Under an argon atmosphere, n-butyl lithium (a 1.58M hexane solution, 400μl, 0.632 mmol) was added to a diethyl ether (3 ml) solution of4-bromo-2-[(t-butyldimethylsilyloxy)methyl]-5-methylpyridine (200 mg,0.632 mmol) at −78° C. The resulting mixture was stirred for 1 hour.After 2,5-difluorobenzaldehyde (69 μl, 0.632 mmol) was added dropwise,the reaction mixture was stirred for 1 hour. To the reaction mixturewere added water and a saturated aqueous solution of sodium bicarbonate,followed by extraction with diethyl ether. The extract was washed withbrine. The organic layer thus obtained was dried over magnesium sulfate,and concentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate=2:1 eluate was concentrated underreduced pressure to give the title compound (178 mg, 0.469 mmol, 74%) asa white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 0.06(3H,s), 0.09(3H,s), 0.91(9H,s), 2.26(3H,s),2.52(1H,brs), 4.79(2H,s), 6.24(1H,s), 6.95-7.10(3H,m), 7.58(1H,s),8.27(1H,s).

MSm/z: 380(M⁺+H).

Example 2052-[(t-Butyldimethylsilyloxy)methyl]-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]-5-methylpyridine

Under an argon atmosphere, triethylamine (4.41 ml, 31.7 mmol) andmethanesulfonyl chloride (2.2 ml, 27.4 mmol) were added to adichloromethane solution (100 ml) of2-[(t-butyldimethylsilyloxy)methyl]-4-[(2,5-difluorophenyl)hydroxymethyl]-5-methylpyridine(8.0 g, 21.1 mmol) under ice cooling. The resulting mixture was stirredat room temperature for 50 minutes. A saturated aqueous solution ofsodium bicarbonate was added to the reaction mixture, followed byextraction with diethyl ether. The extract was washed with brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure.

To a dimethylformamide (100 ml) solution of the residue thus obtainedwere added 4-chlorobenzenethiol (3.66 g, 25.3 mmol) and potassiumcarbonate (4.38 g, 31.7 mmol). The resulting mixture was stirred at 50°C. for 1.5 hours. After cooling to room temperature, the reactionmixture was diluted with diethyl ether. The diluted solution was washedsequentially with water and brine. The organic layer thus obtained wasdried over magnesium sulfate, and concentrated under reduced pressure.The residue thus obtained was subjected to silica gel columnchromatography. The fraction obtained from the hexane:ethyl acetate=5:1eluate was concentrated under reduced pressure to give the titlecompound (9.3 g, 18.4 mmol, 87%) as a pale yellow oil.

¹H-NMR(400 MHz,CDCl₃)δ: 0.04(3H,s), 0.08(3H,s), 0.91(9H,s), 2.33(3H,s),4.77(2H,d,J=4.2 Hz), 5.83(1H,s), 6.92-7.00(2H,m), 7.20(4H,s),7.33-7.38(1H,m), 7.56(1H,s), 8.29(1H,s).

MSm/z: 506(M⁺+H).

Example 206[4-[(4-Chlorophenylthio)(2,5-difluorophenyl)methyl]-5-methylpyridin-2-yl]methanol

To a tetrahydrofuran solution (3 ml) of2-[(t-butyldimethylsilyloxy)methyl]-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]-5-methylpyridine(200 mg, 0.395 mmol) was added tetrabutylammonium fluoride (a 1.0Mtetrahydrofuran solution, 593 μl, 0.593 mmol). The resulting mixture wasstirred for 20 minutes. Water was added to the reaction mixture,followed by extraction with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=3:1 eluate was concentrated under reduced pressureto give the title compound (150 mg, 0.384 mmol, 97%) as a colorless oil.

¹H-NMR(400 MHz,CDCl₃)δ: 2.31(3H,s), 3.54(1H,brs), 4.72(2H,s),5.81(1H,s), 6.94-7.03(2H,m), 7.20(4H,s), 7.22-7.28(1H,m), 7.33(1H,s),8.35(1H,s).

MSm/z: 392 (M⁺+H).

Example 207[4-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-methylpyridin-2-yl]methanol

To a methanol (150 ml) solution of[4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]-5-methylpyridin-2-yl]methanol(6.5 g, 16.6 mmol) were added hexaammonium heptamolybdate tetrahydrate(500 mg) and 30% aqueous hydrogen peroxide (150 ml). The resultingmixture was stirred for 23 hours. Water was added to the reactionmixture. The solid thus precipitated was collected by filtration, andthen washed with water. The resulting solid was dissolved in ethylacetate. The resulting solution was washed with water and brine. Theorganic layer was concentrated under reduced pressure. The residue thusobtained was subjected to silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate=1:1 eluate was concentrated underreduced pressure to give the title compound (4.0 g, 9.44 mmol, 57%) as awhite powder.

¹H-NMR(400 MHz,CDCl₃)δ: 2.13(3H,s), 3.53(1H,brs), 4.80(1H,d,J=14.4 Hz),4.85(1H,d,J=14.4 Hz), 5.88(1H,s), 6.90-6.96(1H,m), 7.01-7.07(1H,m),7.43(2H,d,J=8.8 Hz), 7.60(2H,d,J=8.8 Hz), 7.60(2H,d,J=8.8 Hz),7.63-7.67(1H,m), 7.93(1H,s), 8.36(1H,s).

IR(ATR)cm⁻¹: 3179, 1604, 1573, 1492, 1427, 1394, 1349, 1322, 1280, 1234,1151, 1085, 039, 1010.

mp: 196 to 198° C.

MSm/z: 424(M⁺+H).

Elemental Analysis for C₂₀H₁₆ClF₂NO₃S: Calculated: C, 56.67; H, 3.80;Cl, 8.36; F, 8.96; N, 3.30; S, 7.56. Found: C, 56.41; H, 3.83; Cl, 8.28;F, 8.89; N, 3.31; S, 7.67.

Example 208[4-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-methylpyridin-2-yl]carbaldehyde

Under a nitrogen atmosphere, dimethyl sulfoxide (164 μl, 2.36 mmol),triethylamine (329 μl, 2.36 mmol) and sulfur trioxide pyridine complex(255 mg, 1.42 mmol) were added to a dichloromethane (5 ml) solution of[4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-methylpyridin-2-yl]methanol(200 mg, 0.472 mmol). The resulting mixture was stirred at roomtemperature for 16 hours. The reaction mixture was concentrated underreduced pressure. The residue thus bobtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=3:1 eluate was concentrated under reduced pressureto give the title compound (160 mg, 0.379 mmol, 80%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 2.29(3H,s), 5.94(1H,s), 6.92-6.97(1H,m),7.02-7.08(1H,m), 7.43(2H,d,J=8.8 Hz), 7.62(2H,d,J=8.8 Hz),7.70-7.75(1H,m), 8.57(1H,s), 8.59(1H,s), 10.08(1H,s).

MSm/z: 422 (M⁺+H).

Example 2094-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-methylpicolinicacid

To a formic acid (3 ml) solution of[4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-methylpyridin-2-yl]carbaldehyde(150 mg, 0.356 mmol) was added 30% aqueous hydrogen peroxide (121 μl,1.07 mmol). The resulting mixture was stirred at room temperature for 2hours. Water was added to the reaction mixture. The solid thusprecipitated was collected by filtration and washed with water. Theresulting solid was dissolved in ethyl acetate. The resulting solutionwas washed sequentially with water and brine. The organic layer thusobtained was dried over magnesium sulfate, and concentrated underreduced pressure. The residue thus obtained was recrystallized fromethanol to give the title compound (140 mg, 0.320 mmol, 90%) as a whitepowder.

¹H-NMR(400 MHz,CDCl₃)δ: 2.33(3H,s), 5.96(1H,s), 6.92-6.98(1H,m),7.02-7.08(1H,s), 7.44(2H,d,J=8.6 Hz), 7.64(2H,d,J=8.6), 7.74-7.78(1H,m),8.45(1H,s), 8.81(1H,s).

IR(ATR)cm⁻¹: 1922, 1683, 1598, 1488, 1450, 1428, 1396, 1375, 1326, 1290,1236, 1174, 47, 1085, 1047, 1014.

mp: 105 to 107° C.

MSm/z: 438(M⁺+H).

Elemental Analysis for C₂₀H₁₄ClF₂NO₄S.0.75H₂O: Calculated: C, 53.22; H,3.46; Cl, 7.85; F, 8.42; N, 3.10; S, 7.10. Found: C, 53.44; H, 3.90; Cl,7.47; F, 8.06; N, 3.07; S, 6.95.

Example 210t-Butyl[4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-methylpyridin-2-yl]carbamate

Under an argon atmosphere, diphenylphosphoryl azide (2.9 ml, 13.6 mmol)and triethylamine (2.7 ml, 19.4 mmol) were added to a solution of4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-methylpicolinicacid (2.8 mg, 6.40 mmol) in a mixture of t-butanol (20 ml) and toluene(40 ml). The resulting mixture was stirred for 16 hours under heatingand refluxing. After cooling, ethyl acetate was added to the reactionmixture. The resulting mixture was washed sequentially with a saturatedaqueous solution of sodium bicarbonate and brine. The organic layer thusobtained was dried over magnesium sulfate, and concentrated underreduced pressure. The residue thus obtained was washed sequentially withhexane and ethyl acetate to give the title compound (2.60 g, 5.11 mmol,80%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 1.58(9H,s), 2.07(3H,s), 5.88(1H,s),6.92-6.98(1H,m), 7.00-7.06(1H,m), 7.42(2H,d,J=8.8 Hz), 7.42(2H,d,J=8.8Hz), 7.57(1H,brs), 7.67-7.72(1H,m), 7.71(2H,d,J=8.8 Hz), 8.02(1H,s),8.67(1H,s).

MSm/z: 509(M⁺+H).

Example 211[4-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-methylpyridin-2-yl]amine

To an ethanol (5 ml) solution oft-butyl[4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-methylpyridin-2-yl]carbamate(200 mg, 0.393 mmol) was added concentrated hydrochloric acid (6 ml).The resulting mixture was stirred at room temperature for 2.5 hours. Thereaction mixture was concentrated under reduced pressure. To the residuethus obtained was added a saturated aqueous solution of sodiumbicarbonate, followed by extraction with ethyl acetate. The organiclayer was washed sequentially with water and brine, dried over magnesiumsulfate, and concentrated under reduced pressure. The residue thusobtained was recrystallized from hexane:ethyl acetate to give the titlecompound (125 mg, 0.306 mmol, 78%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 1.89(3H,s), 5.95-5.96(3H,m), 7.12(1H,s),7.22-7.34(2H,m), 7.51-7.55(1H,m), 7.65(2H,d,J=8.8 Hz), 7.69(1H,s),7.78(2H,d,J=8.8 Hz).

IR(ATR)cm⁻¹: 3424, 1637, 1554, 1492, 1457, 1411, 1309, 1276, 1230, 1151,1089, 1039, 1008.

mp: 188 to 189° C.

Elemental Analysis for C₁₉H₁₅ClF₂N₂O₂S: Calculated: C, 55.82; H, 3.70;Cl, 8.67; F, 9.29; N, 6.85; S, 7.84. Found: C, 55.58; H, 3.95; Cl, 8.61;F, 9.13; N, 6.91; S, 7.89.

Example 212N-[4-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-methylpyridin-2-yl]methanesulfonamide

To a methylene chloride (5 ml) solution of[4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-methylpyridin-2-yl]amine(133 mg, 0.325 mmol) and pyridine (39 μl, 0.488 mmol) was addedmethanesulfonyl chloride (28 μl, 0.358 mmol) under ice cooling. Thereaction mixture was stirred at room temperature for 2.5 hours. To thereaction mixture were added pyridine (26 μl, 0.325 mmol) andmethanesulfonyl chloride (25 μl, 0.325 mmol). After the resultingmixture was stirred at room temperature for 16 hours, pyridine (26 μl,0.325 mmol) and methanesulfonyl chloride (25 μl, 0.325 mmol) were addedthereto. The resulting mixture was stirred at room temperature for 1.5hours. The reaction mixture was concentrated under reduced pressure. Tothe residue thus obtained was added ethyl acetate. The resulting mixturewas washed sequentially with water and brine, dried over anhydroussodium sulfate and filtered. The filtrate was concentrated under reducedpressure. The residue thus obtained was subjected to flash silica gelcolumn chromatography. The fraction obtained from the hexane:ethylacetate=3:2 eluate was concentrated under reduced pressure to give thetitle compound (108 mg, 0.222 mmol, 68%) as a white solid. The resultingwhite solid was washed with hexane-ether, and collected by filtration togive the title compound (67 mg) as a white powder.

¹H-NMR(400 MHz,CDCl₃): 2.13(3H,s), 3.29(3H,s), 5.85(1H,s),6.89-6.99(1H,m), 7.01-7.10(1H,m), 7.45(2H,d,J=8.3 Hz), 7.59-7.69(3H,m),7.90(1H,s), 8.12(1H,s).

mp: 214 to 217° C.

MSm/z: 486(M⁺).

Elemental Analysis for C₂₀H₁₇N₂O₄ClF₂S₂: Calculated: C, 49.33; H, 3.52;N, 5.75; Cl, 7.28; F, 7.80; S, 13.17. Found: C, 49.18; H, 3.45; N, 5.82;Cl, 7.18; F, 7.98; S, 13.14.

Example 2132,5-Dichloro-4-[(2,5-difluorophenyl)-(4-fluorophenylthio)methyl]pyridine

The 2,5-dichloro-4-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (1.22 g,4.8 mmol) obtained in Referential Example 24 was dissolved in thionylchloride (5.0 ml). To the resulting solution was added a catalyticamount of dimethylformamide and the resulting mixture was stirred for 4hours. The reaction mixture was concentrated under reduced pressure. Tothe residue was added 1,4-dioxane, followed by further concentration.

The residue thus obtained was dissolved in dimethylformamide (10 ml). Tothe resulting solution were added 4-fluorobenzenethiol (730 mg, 5.7mmol) and potassium carbonate (2.07 g, 15 mmol) under a nitrogenatmosphere. The resulting mixture was stirred at room temperature for 24hours. To the reaction mixture was added diethyl ether (120 ml). Theresulting mixture was washed with water and brine. The organic layer wasdried over magnesium sulfate, and concentrated under reduced pressure.The residue thus obtained was crystallized in ethanol to give the titlecompound (950 mg, 49%) as colorless needle crystals.

¹H-NMR(400 MHz,CDCl₃)δ: 5.92(1H,s), 6.94-7.04(4H,m), 7.19(1H,m),7.33-7.4(2H,m), 7.57(1H,s), 8.33(1H,s).

IR(ATR)cm⁻¹: 1571, 1489, 1329, 1222, 1157, 1109, 835.

mp: 95 to 97° C.

MSm/z: 400(M⁺+H).

Example 214[5-Chloro-4-[(2,5-difluorophenyl)-(4-fluorophenylsulfonyl)methyl]pyridin-2-yl](3,4-dimethoxybenzyl)amine

A 1,4-dioxane (3.0 ml) solution of2,5-dichloro-4-[(2,5-difluorophenyl)-(4-fluorophenylthio)methyl]pyridine(740 mg, 1.85 mmol) and 3,4-dimethoxybenzylamine (836 μl, 5.55 mmol) wasstirred at 120° C. for 3 days under an argon atmosphere in a sealedtube. After cooling to room temperature, ethyl acetate (80 ml) was addedto the reaction mixture. The resulting mixture was washed with brine,dried and concentrated under reduced pressure. The residue thus obtainedwas purified by silica gel chromatography (hexane:ethyl acetate=3:1) togive an amine compound (235 mg) as an oil.

The resulting compound was dissolved in methanol (9.0 ml). To theresulting solution were added hexaammonium heptamolybdate tetrahydrate(30 mg) and 30% aqueous hydrogen peroxide (3.0 ml). The resultingmixture was stirred at room temperature for 20 hours. After dilutionwith ethyl acetate (80 ml), the diluted solution was washed with waterand brine, dried and concentrated under reduced pressure. To the residuethus obtained was added ethanol, followed by crystallization to give thetitle compound (159 mg, 15%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 3.89(6H,s), 4.50(2H,m), 6.10(1H,s),6.85-7.05(5H,m), 7.11(2H,t,J=8.4 Hz), 7.25-7.35(1H,m), 7.29(1H,s),7.61(2H,dd,J=5.2,8.4), 7.99(1H,s).

IR(ATR)cm⁻¹: 3249, 1589, 1490, 1236, 1147, 817.

mp: 158 to 159° C.

MSm/z: 563(M⁺+H).

Example 215[5-Chloro-4-[(2,5-difluorophenyl)-(4-fluorophenylsulfonyl)methyl]pyridin-2-yl]amine

[5-Chloro-4-[(2,5-difluorophenyl)-(4-fluorophenylsulfonyl)methyl]pyridin-2-yl](3,4-dimethoxybenzyl)amine(157 mg, 0.28 mmol) was dissolved in trifluoroacetic acid (5.0 ml). Theresulting solution was stirred at 65° C. for 17 hours. After cooling,the reaction mixture was concentrated under reduced pressure. To theresidue thus obtained was added a saturated aqueous solution of sodiumbicarbonate. The resulting mixture was extracted with ethyl acetate. Theextract was washed with brine, dried and concentrated under reducedpressure. The residue thus obtained was purified by silica gelchromatography (hexane:ethyl acetate=3:1) to give the title compound(114 mg, 99%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 4.76(2H,br), 6.12(1H,s), 6.91(1H,m), 7.06(1H,m),7.14(2H,t,J=8.4), 7.37(1H,s), 7.53(1H,m), 7.69(2H,dd,J=4.8,8.4 Hz),7.98(1H,s).

IR(ATR)cm⁻¹: 3456, 3167, 1639, 1591, 1491, 1417, 1327, 1238, 1140, 1084.

mp: 157 to 159° C.

MSm/z: 413(M⁺+H).

Elemental Analysis for C₁₈H₁₂ClF₃N₂O₂S: Calculated: C, 52.37; H, 2.93;Cl, 8.59; F, 13.81; N, 6.79; S, 7.77. Found: C, 52.45; H, 2.96; Cl,8.62; F, 13.69; N, 6.82; S, 7.83.

Example 216N-[5-Chloro-4-[(2,5-difluorophenyl)-(4-fluorophenylsulfonyl)methyl]pyridin-2-yl]methanesulfonamide

To a methylene chloride solution (10.0 ml) of[5-chloro-4-[(2,5-difluorophenyl)-(4-fluorophenylsulfonyl)methyl]pyridin-2-yl]amine(114 mg, 0.276 mmol) was added pyridine (440 μl, 5.5 mmol). To theresulting mixture was added methanesulfonyl chloride (addition of 77 μlonce a day for 3 days, 230 μl in total, 3.0 mmol). The resulting mixturewas stirred for 4 days in total. The reaction mixture was concentratedunder reduced pressure. The residue thus obtained was purified by silicagel chromatography (hexane:ethyl acetate=2:1), followed bycrystallization in ether to give the title compound (51 mg, 38%) as awhite solid.

¹H-NMR(400 MHz,CDCl₃)δ: 3.35(3H,s), 6.19(1H,s), 6.92(1H,m), 7.08(1H,m),7.15(2H,t,J=8.8 Hz), 7.50(1H,m), 7.73(2H,m), 8.00(1H,s), 8.32(1H,s),

MSm/z: 491(M⁺+H).

IR(ATR)cm⁻¹: 1590, 1490, 1330, 1149, 968, 852. mp: 178 to 179° C.

Elemental Analysis for C₁₉H₁₄ClF₃N₂O₄S₂: Calculated: C, 46.49; H, 2.87;N, 5.71; S, 13.06; Cl, 7.22; F, 11.61. Found: C, 46.55; H, 2.96; N,5.73; S, 13.02; Cl, 7.13; F, 11.39.

Example 217 Optical resolution ofN-[5-chloro-4-[(2,5-difluorophenyl)(4-fluorophenylsulfonyl)methyl]pyridin-2-yl]methanesulfonamide(Optical Isomer A; Optical Isomer B)

TheN-[5-chloro-4-[(2,5-difluorophenyl)(4-fluorophenylsulfonyl)methyl]pyridin-2-yl]methanesulfonamideobtained in Example 216 was optically resolved under the below-describedconditions by using supercritical chromatography (product of Gilson)using a chiral column. Column: CHIRALPAK AD, 2.0 cmφ×25 cm, product ofDaicel Chemical Industries, Ltd.

Mobile phase: 2-propanol:carbon dioxide=1:99→50:50 (three minutes andafter, 50:50)

Flow rate: 6.0 ml/min

Pressure: 14 MPa

Temperature: 35° C.

Detection: UV (254 nm)

The retention time and apparatus data of each optical isomer will nextbe descried.

Optical Isomer A: 16.3 Minutes

¹H-NMR(400 MHz,CDCl₃)δ: 3.35(3H,s), 6.18(1H,s), 6.89-6.97(1H,m),7.02-7.10(1H,m), 7.12-7.20(2H,m), 7.47-7.54(1H,m), 7.69-7.76(2H,m),7.83(1H,brs), 7.98(1H,s), 8.32(1H,s).

Optical Isomer B: 18.4 Minutes

¹H-NMR(400 MHz,CDCl₃)δ: 3.36(3H,s), 6.18(1H,s), 6.89-6.96(1H,m),7.02-7.10(1H,m), 7.12-7.20(2H,m), 7.46-7.54(1H,m), 7.69-7.76(2H,m),7.99(1H,s), 8.32(1H,s).

[α]_(D) ²⁵: +102.6° (c=0.5, CHCl₃).

Example 218 Sodium salt ofN-[5-chloro-4-[(4-chlorophenylsulfinyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]methanesulfonamide

To an ethanol (100 ml) solution of theN-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]methanesulfonamide(15.1 g, 29.8 mmol) obtained in Example 197 was added a 1N aqueoussodium hydroxide solution (32.8 ml). The resulting mixture wasconcentrated under reduced pressure. To the residue thus obtained wasadded 2-propanol to dissolve the former in the latter while warming. Theresulting solution was allowed to stand at room temperature. The solidthus precipitated was collected by filtration to give the title compound(9.10 g, 16.6 mmol, 56%).

¹H-NMR(400 MHz,DMSO-d₆)δ: 2.79(3H,s), 6.10(1H,s), 7.14(1H,s),7.23-7.40(2H,m), 7.48-7.57(1H,m), 7.68(2H,d,J=8.8 Hz), 7.75(2H,d,J=8.8Hz), 7.89(1H,s).

IR(ATR)cm⁻¹: 1583, 1494, 1463, 1384, 1326, 1230, 1151, 1108, 1089, 1012,813, 755.

Elemental Analysis for C₁₉H₁₃N₂O₄Cl₂F₂S₂Na.1.0H₂O: Calculated: C, 41.69;H, 2.76; N, 5.12; Cl, 12.95; F, 6.94; S, 11.72. Found: C, 41.77; H,2.66; N, 5.18; Cl, 13.02; F, 7.03; S, 11.78.

Example 219[5-Chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine

A trifluoroacetic acid (5 ml) solution of the5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]-2-(3,4-dimethoxybenzylamino)pyridine(1.89 g, 3.45 mmol) obtained in Example 185 was stirred at 65° C. for 2hours. The reaction mixture was concentrated under reduced pressure. Tothe residue thus obtained was added a saturated aqueous solution ofsodium bicarbonate, followed by extraction with methylene chloride. Theorganic layer was dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure. The residue thusobtained was subjected to silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate (=2:1) eluate was concentratedunder reduced pressure to yield a white solid. The resulting white solidwas washed with hexane-ether, and collected by filtration to give thetitle compound (1.06 g, 2.67 mmol, 77%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 4.50(2H,s), 5.96(1H,s), 6.76(1H,s),6.90-7.10(2H,m), 7.12-7.35(5H,m), 8.02(1H,s).

IR(ATR)cm⁻¹: 3129, 1635, 1602, 1540, 1490, 1469, 1415, 1093, 1012, 819,728.

MS m/z: 397(M⁺+H).

Example 220N-[5-Chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]-N-(methylsulfonyl)methanesulfonamide(Compound A), andN-[5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]methanesulfonamide(Compound B)

To a pyridine (5 ml) solution of[5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine(575 mg, 1.45 mmol) was added methanesulfonyl chloride (0.123 ml, 1.59mmol) at 0° C. The resulting mixture was stirred at room temperature for16 hours. To the reaction mixture was added methanesulfonyl chloride(0.123 ml, 1.59 mmol) at 0° C. The resulting mixture was stirred at roomtemperature for 22 hours. To the reaction mixture was added pyridine (3ml), followed by further addition of methanesulfonyl chloride (0.123 ml,1.59 mmol) at 0° C. After stirring at room temperature for 25 hours, thereaction mixture was concentrated under reduced pressure. The residuethus obtained was diluted with ethyl acetate. The diluted solution waswashed sequentially with water and brine, dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated under reducedpressure. The residue thus obtained was subjected to flash silica gelcolumn chromatography. The fraction obtained from the hexane:ethylacetate (=4:1) eluate was concentrated under reduced pressure to givethe title Compound A (low polar compound) (334 mg, 0.603 mmol, 42%) asan amorphous substance and the title Compound B (high polar compound)(269 mg, 0.566 mmol, 39%) as a white solid.

Compound A

¹H-NMR(400 MHz,CDCl₃)δ: 3.56(6H,s), 5.97(1H,s), 6.95-7.09(3H,m),7.20-7.31(4H,m), 7.76(1H,s), 8.45(1H,s).

IR(ATR)cm⁻¹: 1583, 1492, 1367, 1321, 1159, 1093, 1006, 962, 931, 821,759.

MS m/z: 552(M⁺).

Compound B

¹H-NMR(400 MHz,CDCl₃)δ: 3.15(3H,s), 6.02(1H,s), 6.94-7.13(3H,m),7.20-7.35(4H,m), 7.59(1H,s), 8.07(1H,brs), 8.30(1H,s).

mp: 149 to 151° C.

IR(ATR)cm⁻¹: 1590, 1556, 1488, 1475, 1380, 1348, 1149, 993, 962, 831,784.

MS m/z: 475(M⁺+H).

FAB-MS: 474.9925 (Calcd for C₁₉H₁₅O₂N₂Cl₂F₂S₂: 474.9920).

Elemental Analysis for C₁₉H₁₄N₂O₂Cl₂F₂S₂: Calculated: C, 48.01; H, 2.97;N, 5.89; Cl, 14.92; F, 7.99; S, 13.49. Found: C, 48.27; H, 2.95; N,5.91; Cl, 14.79; F, 7.96; S, 13.61.

Example 221N-[5-Chloro-4-[(4-chlorophenylsulfinyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]methanesulfonamide

To a methylene chloride (10 ml) solution ofN-[5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]methanesulfonamide(331 mg, 0.696 mmol) was added 3-chloroperbenzoic acid (120 mg, 0.696mmol) at 0° C. The resulting mixture was stirred at 0° C. for 50minutes. At the same temperature, 3-chloroperbenzoic acid (60 mg, 0.348mmol) was added to the reaction mixture. After stirring at 0° C. for 10minutes, a saturated aqueous solution of sodium thiosulfate was added tothe reaction mixture. The resulting mixture was extracted with methylenechloride. The organic layer was dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure. Theresidue thus obtained was subjected to flash silica gel columnchromatography. The fraction obtained from the hexane:ethyl acetate(=2:1) eluate was concentrated under reduced pressure. To the residuethue obtained was added ether and the solid thus precipitated wascollected by filtration to give the title compound (281 mg, 0.572 mmol,82%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 3.36(3H,s), 5.48(0.5H,s), 5.66(0.5H,s),6.79-6.88(0.5H,m), 6.95-7.09(1.5H,m), 7.18-7.44(5H,m), 7.64(0.5H,s),7.83(0.5H,s), 8.23(0.5H,s), 8.36(0.5H,s), 8.70(1H,brs).

IR(ATR)cm⁻¹: 3124, 3081, 1594, 1492, 1463, 1334, 1143, 964, 871, 821,742.

MS m/z: 491(M⁺+H).

FAB-MS: 490.9853 (Calcd for C₁₉H₁₅O₃N₂Cl₂F₂S₂: 490.9869).

Elemental Analysis for C₁₉H₁₄N₂O₃Cl₂F₂S₂: Calculated: C, 46.44; H, 2.87;N, 5.70; Cl, 14.43; F, 7.73; S, 13.05. Found: C, 46.64; H, 3.02; N,5.64; Cl, 14.31; F, 7.74; S, 13.02.

Example 222[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]hydrazine

To an ethanol (10 ml) solution of the2,5-dichloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridine(524 mg, 1.17 mmol) obtained in Example 57 was added hydrazinemonohydrate (2 ml). The resulting mixture was heated under reflux for 3hours. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue thus obtained wassubjected to silica gel column chromatography. The fraction obtainedfrom the hexane:ethyl acetate (=1:1) eluate was concentrated underreduced pressure to afford a pale yellow oil. To the resulting oil wasadded hexane-ether and the solid thus precipitated was collected byfiltration to give the title compound (95 mg, 0.214 mmol, 18%) as awhite powder.

¹H-NMR(400 MHz,CDCl₃)δ: 3.89(2H,s), 6.03(1H,s), 6.16(1H,s),6.89-6.97(1H,m), 7.00-7.09(1H,m), 7.44(2H,d,J=8.8 Hz), 7.50-7.58(1H,m),7.60-7.68(3H,m), 8.03(1H,s).

IR(ATR)cm⁻¹: 3249, 1590, 1550, 1492, 1413, 1315, 1174, 1149, 1083, 811,754.

MS m/z: 443(M⁺).

Elemental Analysis for C₁₈H₁₃N₃O₂Cl₂F₂S: Calculated: C, 48.66; H, 2.95;N, 9.46; Cl, 15.96; F, 8.55; S, 7.22. Found: C, 48.48; H, 2.81; N, 9.40;Cl, 15.80; F, 8.59; S, 7.23.

Example 223 t-ButylN′-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]hydrazinecarboxylate

To a methylene chloride (5 ml) solution of[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]hydrazine(166 mg, 0.374 mmol) was added di-t-butyl dicarbonate (122 mg, 0.560mmol). The resulting mixture was stirred at room temperature for 16hours. The reaction mixture was concentrated under reduced pressure. Theresidue thus obtained was subjected to flash silica gel columnchromatography. The fraction obtained from the hexane:ethyl acetate(=3:1) eluate was concentrated under reduced pressure to give the titlecompound (166 mg, 0.305 mmol, 82%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 1.51(9H,s), 6.19(1H,s), 6.42(1H,s),6.59(1H,brs), 6.91-7.09(2H,m), 7.43(2H,d,J=8.8 Hz), 7.50-7.56(1H,m),7.57(1H,s), 7.63(2H,d,J=8.8 Hz), 8.06(1H,s).

IR(ATR)cm⁻¹: 3336, 3295, 1681, 1596, 1558, 1496, 1477, 1321, 1151, 1091,809.

MS m/z: 544(M⁺+H).

Example 224 t-ButylN′-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]-N′-methylsulfonylhydrazinecarboxylate

To a methylene chloride (5 ml) solution of t-butylN′-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]hydrazinecarboxylate (178 mg, 0.327 mmol) and triethylamine (43 μl, 0.392 mmol)was added methanesulfonyl chloride (30 μl, 0.392 mmol) at 0° C. Theresulting mixture was stirred at room temperature for 16 hours. To thereaction mixture were added triethylamine (43 μl, 0.392 mmol) andmethanesulfonyl chloride (30 μl, 0.392 mmol). After stirring at roomtemperature for 3 hours, the reaction mixture was concentrated underreduced pressure. The residue thus obtained was diluted with ethylacetate. The diluted solution was washed sequentially with a saturatedaqueous solution of sodium bicarbonate and brine, dried over anhydroussodium sulfate and filtered. The filtrate was concentrated under reducedpressure. The residue thus obtained was subjected to flash silica gelcolumn chromatography. The fraction obtained from the hexane:ethylacetate (=4:1) eluate was concentrated under reduced pressure to givethe title compound (174 mg, 0.280 mmol, 85%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 1.52(9H,s), 3.56(3H,s), 6.21(1H,s),6.92-7.10(2H,m), 7.31(1H,brs), 7.44(2H,d,J=8.7 Hz), 7.47-7.54(1H,m),7.63(2H,d,J=8.7 Hz), 8.05(1H,s), 8.28(1H,s).

IR(ATR)cm⁻¹: 3320, 1731, 1583, 1494, 1353, 1326, 1236, 1149, 1091, 958,754, 728.

MS m/z: 622(M⁺+H).

Example 2251-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]-1-methylsulfonylhydrazine

To a methylene chloride (5 ml) solution of t-butylN′-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]-N′-methylsulfonylhydrazinecarboxylate (167 mg, 0.268 mmol) was added trifluoroacetic acid (2.5ml). The resulting mixture was stirred at room temperature for 21 hours,followed by concentration under reduced pressure. To the residue thusobtained was added a saturated aqueous solution of sodium bicarbonate.The resulting mixture was extracted with methylene chloride. The organiclayer obtained by separation was dried over anhydrous sodium sulfate,and filtered. The filtrate was concentrated under reduced pressure. Theresidue thus obtained was subjected to flash silica gel columnchromatography. The fraction obtained from the hexane:ethyl acetate(=2:1) eluate was concentrated under reduced pressure to afford thetitle compound (91 mg, 0.174 mmol, 65%) as a white solid. The resultingsolid was washed with ether and collected by filtration to give thetitle compound (60 mg) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 3.25(3H,s), 4.80(2H,brs), 6.25(1H,s),6.90-7.10(2H,m), 7.44(2H,d,J=8.6 Hz), 7.53-7.61(1H,m), 7.68(2H,d,J=8.6Hz), 8.32(1H,s), 8.44(1H,s).

mp: 152 to 154° C.

IR(ATR)cm⁻¹: 1583, 1490, 1361, 1319, 1149, 1079, 958, 833, 754.

MS m/z: 522(M⁺+H).

Elemental Analysis for C₁₉H₁₅N₃O₄Cl₂F₂S₂: Calculated: C, 43.69; H, 2.89;N, 8.04; Cl, 13.57; F, 7.27; S, 12.28. Found: C, 43.86; H, 2.93; N,7.91; Cl, 13.19; F, 7.31; S, 12.28.

Referential Example 412,5-Dibromo-4-[(2,5-difluorophenyl)hydroxymethyl]pyridine

Under an argon atmosphere, n-butyl lithium (a 1.59M hexane solution, 76ml, 121 mmol) was added to a tetrahydrofuran (400 ml) solution ofdiisopropylamine (17 ml, 121 mmol) at −70° C. The reaction mixture wasstirred for 1 hour. To the reaction mixture was added dropwise atetrahydrofuran (100 ml) solution of 2,5-dibromopyridine and theresulting mixture was stirred for 2 hours. To the reaction mixture wasadded dropwise 2,5-difluorobenzaldehyde (15 ml, 139 mmol) and themixture was stirred for 1 hour. After addition of water, the resultingmixture was concentrated under reduced pressure. The residue thusobtained was extracted with dichloromethane. The organic layer thusobtained was dried over magnesium sulfate, and concentrated underreduced pressure. The residue thus obtained was washed withdichloromethane:hexane to yield a pale yellow powder. The filtrate wassubjected to silica gel column chromatography. The fraction obtainedfrom the hexane:ethyl acetate=6:1 eluate was concentrated under reducedpressure. The residue thus obtained and the above-described pale yellowpowder were combined to give the title compound (18.4 g, 48.6 mmol, 52%)as a pale yellow powder.

¹H-NMR(400 MHz,CDCl₃)δ: 2.62(1H,s), 6.24(1H,s), 6.85-6.89(1H,m),7.00-7.10(2H,m), 7.79(1H,s), 8.43(1H,s).

MS m/z: 378(M⁺+H).

Example 2262,5-Dibromo-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine

Under an argon atmosphere, triethylamine (5.1 ml, 36.8 mmol) andmethanesulfonyl chloride (2.6 ml, 31.9 mmol) were added to adichloromethane solution (200 ml) of2,5-dibromo-4-[(2,5-difluorophenyl)hydroxymethyl]pyridine (9.3 g, 24.5mmol) under ice cooling. The reaction mixture was stirred at roomtemperature for 30 minutes. After addition of water, the resultingmixture was concentrated under reduced pressure. The residue thusobtained was extracted with diethyl ether. The organic layer was washedwith brine, dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure.

To a dimethylformamide (200 ml) solution of the residue thus obtainedwere added 4-chlorobenzenethiol (4.3 g, 29.4 mmol) and potassiumcarbonate (5.1 g, 36.8 mmol). The resulting mixture was stirred at roomtemperature for 17 hours. After addition of water, the resulting mixturewas extracted with diethyl ether. The organic layer was washed withbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue thus obtained was washed with hexane toafford a white powder. The filtrate was subjected to flash silica gelcolumn chromatography. The fraction obtained from the dichloromethaneeluate was concentrated under reduced pressure. The residue thusobtained and the above-described white powder were combined to give thetitle compound (9.1 g, 18.0 mmol, 73%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 5.94(1H,s), 7.00-7.05(2H,m), 7.15-7.20(1H,m),7.25(2H,d,J=8.6 Hz), 7.29(2H,d,J=8.6 Hz), 7.68(1H,s), 8.45(1H,s).

MS m/z: 504(M⁺+H).

Example 227[5-Bromo-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]methanol

Under an argon atmosphere, n-butyl lithium (a 1.59M hexane solution,0.27 ml, 0.435 mmol) was added to a toluene (10 ml) solution of2,5-dibromo-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine(200 mg, 0.396 mmol) at −78° C. The reaction mixture was stirred for 2hours. To the reaction mixture was added dropwise dimethylformamide (40μl, 0.514 mmol), followed by stirring for 1 hour. To the reactionmixture were added methanol (10 ml) and sodium borohydride (30 mg, 0.791mmol). The temperature of the resulting mixture was raised to roomtemperature. The reaction mixture was stirred for 1 hour. After additionof water, the resulting mixture was extracted with ethyl acetate. Theextract was washed with brine. The organic layer thus obtained was driedover magnesium sulfate, and concentrated under reduced pressure. Theresidue thus obtained was subjected to flash silica gel columnchromatography. The fraction obtained from the hexane:ethyl acetate=3:1eluate was concentrated under reduced pressure to give the titlecompound (160 mg, 0.350 mmol, 89%) as a colorless amorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 3.18(1H,t,J=5.2 Hz), 4.72(2H,d,J=5.2 Hz),6.04(1H,s), 6.95-7.05(2H,m), 7.16-7.21(1H,m), 7.22(2H,d,J=7.8 Hz),7.25(2H,d,J=7.8 Hz), 7.51 (1H,s), 8.64(1H,s)

MS m/z: 456(M⁺+H).

Example 228[5-Bromo-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]methanol

To a solution of[5-bromo-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]methanol(550 mg, 1.20 mmol) in a mixture of methanol (10 ml) and ethyl acetate(10 ml) were added hexaammonium heptamolybdate tetrahydrate (100 mg) and30% aqueous hydrogen peroxide (10 ml). The resulting mixture was stirredfor 19 hours. After addition of water, the resulting mixture wasextracted with ethyl acetate. The extract was washed sequentially withwater, a saturated aqueous solution of sodium bicarbonate, a saturatedaqueous solution of sodium thiosulfate and brine. The organic layer thusobtained was dried over magnesium sulfate, and concentrated underreduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure,followed by recrystallization from hexane:ethyl acetate to give thetitle compound (506 mg, 1.04 mmol, 86%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 3.18(1H,t,J=5.0 Hz), 4.79-4.88(2H,m),6.24(1H,s), 6.92-6.97(1H,m), 7.03-7.09(1H,m), 7.45(2H,d,J=8.6 Hz),7.51-7.55(1H,m), 7.61(2H,d,J=8.6 Hz), 8.11(1H,s), 8.65(1H,s).

IR(ATR)cm⁻¹: 3262, 1583, 1492, 1427, 1392, 1330, 1280, 1236, 1157, 1083,1033.

mp: 172 to 173° C.

MS m/z: 488(M⁺+H).

Elemental Analysis for C₁₉H₁₃BrClF₂NO₃S: Calculated: C, 46.69; H, 2.68;Br, 16.35; Cl, 7.25; F, 7.77; N, 2.87; S, 6.56. Found: C, 46.59; H,2.55; Br, 16.31; Cl, 7.05; F, 7.78; N, 2.89; S, 6.70.

Example 229[5-Bromo-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbaldehyde

Under a nitrogen atmosphere, dimethyl sulfoxide (218 μl, 3.07 mmol),triethylamine (428 μl, 3.07 mmol) and sulfur trioxide pyridine complex(293 mg, 1.84 mmol) were added to a dichloromethane (10 ml) solution of[5-bromo-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]methanol(300 mg, 0.614 mmol). The reaction mixture was stirred at roomtemperature for 4 hours. The reaction mixture was concentrated underreduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=3:1 eluate was concentrated under reduced pressureto give the title compound (227 mg, 0.466 mmol, 76%) as a colorlessamorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 6.29(1H,s), 6.93-7.00(1H,m), 7.04-7.10(1H,m),7.44(2H,d,J=8.8 Hz), 7.57-7.62(1H,m), 7.62(2H,d,J=8.8 Hz), 8.68(1H,s),8.88(1H,s), 10.09(1H,s).

MS m/z: 486(M⁺+H).

Example 2305-Bromo-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]picolinicacid

To a formic acid (5 ml) solution of[5-bromo-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbaldehyde(225 mg, 0.462 mmol) was added 30% aqueous hydrogen peroxide (157 μl,1.39 mmol). The resulting mixture was stirred at room temperature for 3hours. To the reaction mixture was added water and the solid thusprecipitated was filtered. The solid thus obtained was washed withwater. The resulting solid was dissolved in ethyl acetate. The resultingsolution was washed sequentially with water and brine. The organic layerthus obtained was dried over magnesium sulfate and concentrated underreduced pressure to give the title compound (226 mg, 0.461 mmol, 97%) asa white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 6.30(1H,s), 6.94-6.99(1H,m), 7.05-7.11(1H,m),7.46(2H,d,J=8.8 Hz), 7.61-7.66(1H,m), 7.65(2H,d,J=8.8 Hz), 8.75(1H,s),8.94(1H,s).

MS m/z: 502(M⁺+H).

Example 231t-Butyl[5-bromo-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbamate

Under an argon atmosphere, diphenylphosphoryl azide (131 μl, 0.613 mmol)and triethylamine (122 μl, 0.875 mmol) were added to a solution of5-bromo-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]picolinicacid (220 mg, 0.438 mmol) in a mixture of t-butanol (5 ml) and toluene(5 ml). The reaction mixture was stirred for 14 hours under heating andrefluxing. After cooling, ethyl acetate was added to the residue. Theresulting mixture was washed sequentially with a saturated aqueoussolution of sodium bicarbonate and brine. The organic layer thusobtained was dried over magnesium sulfate, and concentrated underreduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=4:1 eluate was concentrated under reduced pressureto give the title compound (128 mg, 0.223 mmol, 51%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 1.59(9H,s), 6.23(1H,s), 6.92-7.00(1H,m),7.02-7.08(1H,m), 7.33(1H,brs), 7.43(2H,d,J=8.4 Hz), 7.57-7.62(1H,m),7.71(2H,d,J=8.4 Hz), 8.28(1H,s), 8.86(1H,s).

MS m/z: 573(M⁺+H).

Example 232[5-Bromo-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine

To an ethanol (2 ml) solution oft-butyl[5-bromo-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbamate(130 mg, 0.227 mmol) was added concentrated hydrochloric acid (2 ml).The resulting mixture was stirred at room temperature for 63 hours. Thereaction mixture was concentrated under reduced pressure. To the residuethus obtained was added saturated sodium bicarbonate, followed byextraction with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate, and concentrated under reduced pressure.The residue thus obtained was recrystallized from hexane:ethyl acetateto give the title compound (72 mg, 0.152 mmol, 67%) as a pale yellowpowder.

¹H-NMR(400 MHz,CDCl₃)δ: 4.67(2H,s), 6.12(1H,s), 6.91-6.97(1H,m),7.02-7.08(1H,m), 7.36(1H,s), 7.45(2H,d,J=8.6 Hz), 7.48-7.54(1H,m),7.62(2H,d,J=8.6 Hz), 8.11(1H,s).

IR(ATR)cm⁻¹: 3467, 3372, 1617, 1585, 1540, 1492, 1475, 1413, 1330, 1311,1280, 1238, 1178, 1151, 1081, 1033, 1012.

mp: 204 to 206° C.

MS m/z: 473(M⁺+H).

Elemental Analysis for C₁₈H₁₂BrClF₂N₂O₂S: Calculated: C, 45.64; H, 2.55;Br, 16.87; Cl, 7.48; F, 8.02; N, 5.91; S, 6.77. Found: C, 45.87; H,2.58; Br, 16.61; Cl, 7.56; F, 8.05; N, 5.90; S, 6.90.

Referential Example 42 5-Cyano-2-fluorobenzaldehyde

Diisopropylamine (2.80 ml, 19.8 mmol) was dissolved in tetrahydrofuran(20 ml). At −78° C., a hexane solution (1.60M, 11.4 ml, 18.2 mmol) ofn-butyl lithium was added dropwise to the resulting solution. Thereaction mixture was stirred at the same temperature for 30 minutes,followed by the dropwise addition of a tetrahydrofuran solution (20 ml)of 4-fluorobenzonitrile (2.00 g, 16.5 mmol). After stirring further atthe same temperature for 30 minutes, N,N-dimethylformamide (1.7 ml, 21.5mmol) was added dropwise to the reaction mixture. At the sametemperature, the reaction mixture was stirred for 10 minutes. To thereaction mixture were added acetic acid and a saturated aqueous solutionof ammonium chloride, followed by extraction with ethyl acetate. Theorganic layers were combined and dried over anhydrous sodium sulfate,and filtered. The filtrate was concentrated under reduced pressure. Theresidue thus obtained was subjected to silica gel chromatography. Thefraction obtained from the n-hexane:ethyl acetate=10:2 eluate wasconcentrated under reduced pressure to give the title compound (1.83 g,12.3 mmol, 74%) as a pale yellowish brown oil.

¹H-NMR(400 MHz,CD₃OD)δ: 7.37(1H,t,J=9.0 Hz), 7.92(1H,ddd,J=9.0,6.4,2.2Hz), 8.21(1H,dd,J=6.4,2.2 Hz), 10.4(1H,s).

IR(ATR)cm⁻¹: 1953, 1695, 1600, 1482, 1236, 1105, 846, 624, 580.

MS m/z: 150(M⁺+H).

Referential Example 433-[(2,5-Dichloropyridin-4-yl)hydroxymethyl]-4-fluorobenzonitrile

Diisopropylamine (0.52 ml, 3.70 mmol) was dissolved in tetrahydrofuran(5 ml). At −78° C., a hexane solution (1.54M, 2.20 ml, 3.39 mmol) ofn-butyl lithium was added dropwise to the resulting solution. Thereaction mixture was stirred at the same temperature for 30 minutes. Atetrahydrofuran solution (20 ml) of 2,5-dichloropyridine (0.46 g, 3.08mmol) was added dropwise to the reaction mixture. After stirring furtherat the same temperature for 1 hour, a tetrahydrofuran solution (5 ml) of5-cyano-2-fluorobenzaldehyde (0.46 g, 3.08 mmol) was added dropwise tothe reaction mixture. The resulting mixture was stirred at the sametemperature for 30 minutes. To the reaction mixture was added asaturated aqueous solution of ammonium chloride, followed by extractionwith ethyl acetate. The organic layers were combined, dried overanhydrous magnesium sulfate, and filtered. The filtrate was concentratedunder reduced pressure. The residue thus obtained was subjected tosilica gel chromatography. The fraction obtained from the n-hexane:ethylacetate=10:2 eluate was concentrated under reduced pressure to give thetitle compound (0.68 g, 2.28 mmol, 74%) as a pale yellowish brown oil.

¹H-NMR(400 MHz,CDCl₃)δ: 6.33(1H,s), 7.22(1H,t,J=8.3 Hz),7.60(1H,dd,J=6.6,2.2 Hz), 7.66(1H,s), 7.66-7.69(1H,m), 8.34(1H,s).

IR(ATR)cm⁻¹: 3413, 1577, 1492, 1334, 1247, 1110, 829, 534.

MS m/z: 297(M⁺+H).

Example 2333-[(4-Chlorophenylsulfonyl)(2,5-dichloropyridin-4-yl)methyl]-4-fluorobenzonitrile

Under ice cooling, thionyl chloride (3 ml) and a catalytic amount ofN,N-dimethylformamide were added to a dichloromethane solution (5 ml) of3-[(2,5-dichloropyridin-4-yl)hydroxymethyl]-4-fluorobenzonitrile (677mg, 2.28 mmol). The resulting mixture was stirred at room temperaturefor 4 hours. Water was added to the reaction mixture, followed byextraction with dichloromethane. The organic layers were combined, driedover anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure.

The residue thus obtained was dissolved in N,N-dimethylformamide (5 ml).To the resulting solution was added sodium 4-chlorobenzenesulfinate (905mg, 4.56 mmol). The resulting mixture was stirred at room temperaturefor 20 hours. Water was added to the reaction mixture, followed byextraction with ethyl acetate. The organic layers were combined, driedover anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure. The residue thus obtained wassubjected to silica gel chromatography. The fraction obtained from then-hexane:ethyl acetate=10:2 eluate was concentrated under reducedpressure to give the title compound (170 mg, 0.37 mmol, 16%) as a paleyellowish brown solid.

¹H-NMR(400 MHz,CDCl₃)δ: 6.19(1H,s), 7.15(1H,t,J=8.5 Hz), 7.48(2H,d,J=8.5Hz), 7.62(2H,d,J=8.5 Hz), 7.72(1H,ddd,J=8.5,5.4,2.4 Hz),8.12(1H,dd,J=5.4,2.4 Hz), 8.13(1H,s), 8.36(1H,s).

IR(ATR)cm⁻¹: 1569, 1494, 1315, 1257, 1120, 1081, 752, 617, 570, 536.

MS m/z: 456(M⁺).

Example 2343-[(2-Amino-5-chloropyridin-4-yl)(4-chlorophenylsulfonyl)methyl]-4-fluorobenzonitrile

In N-methylpyrrolidone (12 ml) was dissolved3-[(4-chlorobenzenesulfonyl)(2,5-dichloropyridin-4-yl)methyl]-4-fluorobenzonitrile(559 mg, 1.23 mmol), followed by the addition of3,4-dimethoxybenzylamine (0.91 ml, 6.13 mmol). The resulting mixture wasstirred under heating at 140° C. for 4 hours. Water was added to thereaction mixture, followed by extraction with ethyl acetate. The extractwas washed with brine. The organic layer was dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure. The residue thus obtained was subjected to silica gelchromatography. The fraction obtained from the n-hexane:ethylacetate=2:1 eluate was concentrated under reduced pressure.

The residue thus obtained was dissolved in trifluoroacetic acid (5 ml)and the resulting solution was stirred under heating at 70° C. for 2hours. The reaction mixture was concentrated under reduced pressure. Theresidue thus obtained was subjected to silica gel chromatography. Thefraction obtained from the n-hexane:ethyl acetate=2:1 eluate wasconcentrated under reduced pressure to give the title compound (50 mg0.11 mmol, 9%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 4.74(2H,s), 6.16(1H,s), 7.12(1H,t,J=8.8 Hz),7.32(1H,s), 7.48(2H,d,J=8.5 Hz), 7.62(2H,d,J=8.5 Hz), 7.98(1H,s),8.15(1H,dd,J=8.8,2.0 Hz), 8.55(1H,d,J=2.0 Hz).

IR(ATR)cm⁻¹: 1614, 1475, 1411, 1311, 1259, 1145, 1091, 755, 642, 620,561, 543, 460.

mp: >220° C.

MS m/z: 436(M⁺+H).

Elemental Analysis for C₁₉H₁₂Cl₂FN₃O₂S: Calculated: C, 52.31; H, 2.77;Cl, 16.25; F, 4.35; N, 9.63; S, 7.35. Found: C, 52.17; H, 2.85; Cl,16.50; F, 4.32; N, 9.40; S, 7.30.

Example 235N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(5-cyano-2-fluorophenyl)methyl]pyridin-2-yl]-N-(methylsulfonyl)methanesulfonamide

After3-[(2-amino-5-chloropyridin-4-yl)(4-chlorophenylsulfonyl)methyl]-4-fluorobenzonitrile(50 mg, 0.11 mmol) was dissolved in dichloromethane (5 ml),ethanesulfonyl chloride (27 μl, 0.39 mmol), triethylamine (48 μl, 0.39mmol) and a catalytic amount of 4-dimethylaminopyridine were added tothe resulting solution at 0° C. The resulting mixture was stirred at thesame temperature for 30 minutes. Water was added and the resultingmixture was extracted with dichloromethane. The extract was washed withbrine. The organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure. Theresidue thus obtained was subjected to silica gel chromatography. Thefraction obtained from the n-hexane:ethyl acetate=10:3 eluate wasconcentrated under reduced pressure to give the title compound (80 mg,0.11 mmol, 99%) as a white powder.

¹H-NMR(400 MHz,CDCl₄)δ: 3.65(6H,s), 6.25(1H,s), 7.24(1H,t,J=8.8 Hz),7.45(2H,d,J=8.5 Hz), 7.66(2H,d,J=8.5 Hz), 7.75(1H,ddd,J=8.8,6.6,2.0 Hz),8.16(1H,s), 8.19(1H,dd,J=6.6,2.0 Hz), 8.43(1H,s).

IR(ATR)cm⁻¹: 1725, 1583, 1492, 1369, 1326, 1164, 931, 835, 757, 628,551, 505, 460.

MS m/z: 592(M⁺+H).

Example 236N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(5-cyano-2-fluorophenyl)methyl]pyridin-2-yl]methanesulfonamide

AfterN-[5-chloro-4-[(4-chlorophenylsulfonyl)(5-cyano-2-fluorophenyl)methyl]pyridin-2-yl]-N-(methylsulfonyl)methanesulfonamide(80 mg, 0.11 mmol) was dissolved in tetrahydrofuran (3 ml), atetrahydrofuran solution (1.0M, 0.15 ml, 0.15 mmol) oftetrabutylammonium fluoride was added to the resulting solution at 0° C.The resulting mixture was stirred at room temperature for 1 hour. Theresidue obtained by concentrating the reaction mixture under reducedpressure was subjected to silica gel chromatography. The fractionobtained from the n-hexane:ethyl acetate=2:1 eluate was concentratedunder reduced pressure to afford a white solid. The resulting whitesolid was washed with ether to give the title compound (32 mg, 0.06mmol, 46%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 3.37(3H,s), 6.20(1H,s), 7.14(1H,d,J=8.8 Hz),7.48(2H,d,J=8.5 Hz), 7.62(2H,d,J=8.5 Hz), 7.68-7.72(1H,m), 7.92(1H,s),8.11(1H,dd,J=6.6,2.0 Hz), 8.34(1H,s).

IR(ATR)cm⁻¹: 1596, 1494, 1473, 1328, 1151, 1089, 755, 636, 541, 516.

mp: 118 to 120° C.

MS m/z: 514(M⁺+H).

Elemental Analysis for C₂₀H₁₄Cl₂FN₃O₄S₂: Calculated: C, 46.70; H, 2.74;Cl, 13.78; F, 3.69; N, 8.17; S, 12.47. Found: C, 47.00; H, 2.94; Cl,13.64; F, 3.58; N, 8.15; S, 12.44.

Referential Example 445-Chloro-2-(2,2,5,5-tetramethyl-1,2,5-azadisilolydin-1-yl)pyridine

To a tetrahydrofuran (350 ml) solution of 5-chloropyridin-2-ylamine(10.28 g, 80.0 mmol) was added a hexane solution (1.58M, 50.6 ml, 80.0mmol) of n-butyl lithium at −78° C. The resulting mixture was stirredfor 1 hour. At the same temperature, a tetrahydrofuran (50 ml) solutionof 1,2-bis(chlorodimethylsilyl)ethane (17.22 g, 80.0 mmol) was added tothe reaction mixture, followed by stirring for 1 hour. A hexane solution(1.58M, 50.6 ml, 80.0 mmol) of n-butyl lithium was added at the sametemperature and the resulting mixture was stirred for 30 minutes. Atroom temperature, a saturated aqueous solution of sodium chloride wasadded to the reaction mixture. Diethyl ether was added to the resultingmixture to separate it into layers. The organic layer was dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure. The residue thus obtained was distilled underreduced pressure (120° C./3.0 mmHg) to give the title compound (12.97 g,47.9 mmol, 60%) as a colorless acicular substance.

¹H-NMR(400 MHz,CDCl₃)δ: 0.29(12H,s), 0.82(4H,s), 6.50(1H,d,J=8.8 Hz),7.34(1H,dd,J=8.8,2.7 Hz), 8.05(1H,d,J=2.7 Hz).

Referential Example 45(2-Amino-5-chloropyridin-4-yl)(2,5-difluorophenyl)methanol

To a mixture of a hexane solution (1.58M, 8.41 ml, 13.3 mmol) of n-butyllithium and tetrahydrofuran (40 ml) was added diisopropylamine (1.86 ml,13.3 mmol) at −78° C. After the resulting mixture was stirred at 0° C.for 1 hour, the reaction mixture was cooled to −78° C. To the reactionmixture was added a tetrahydrofuran (10 ml) solution of5-chloro-2-(2,2,5,5-tetramethyl-1,2,5-azadisilolydin-1-yl)pyridine (3.27g, 12.1 mmol). At the same temperature, the resulting mixture wasstirred for 1 hour. Then, a tetrahydrofuran (10 ml) solution of2,5-difluorobenzaldehyde (1.89 g, 13.3 mmol) was added to the reactionmixture. After stirring at the same temperature for 30 minutes, 1Nhydrochloric acid (50 ml) was added at 0° C. To the reaction mixture wasadded a 1N aqueous solution (100 ml) of sodium hydroxide. The productthus obtained was extracted with diethyl ether. The organic layer wasdried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure. The residue thus obtained waswashed with a mixed solvent of dichloromethane/hexane, and collected byfiltration to give the title compound (1.76 g, 6.50 mmol, 54%) as awhite solid.

¹H-NMR(400 MHz,DMSO-d₆)δ: 5.96(1H,d,J=4.9 Hz), 6.17(2H,s),6.31(1H,d,J=4.9 Hz), 6.68(1H,s), 6.97-7.04(1H,m), 7.15-7.29(2H,m),7.82(1H,s).

MS m/z: 271 (M⁺+H).

Referential Example 46(2-Amino-5-chloropyridin-4-yl)(2,5-difluorophenyl)methyl t-butylcarbonate

Under a nitrogen atmosphere, di-t-butyl dicarbonate (3.63 g, 16.6 mmol)and 4-dimethylaminopyridine (203 mg, 1.66 mmol) were added to adichloromethane (150 ml) solution of(2-amino-5-chloropyridin-4-yl)(2,5-difluorophenyl)methanol (4.50 g, 16.6mmol) at room temperature. The resulting mixture was stirred at roomtemperature for 2 hours. The reaction mixture was concentrated underreduced pressure. The residue thus obtained was subjected to flashsilica gel chromatography. The fraction obtained from thedichloromethane:methanol=50:1 eluate was concentrated under reducedpressure to give the title compound (5.70 g, 15.4 mmol, 92%) as a whitesolid.

¹H-NMR(400 MHz,CDCl₃)δ: 1.49(9H,s), 4.53(2H,s), 6.66(1H,s),6.89-6.95(1H,m), 6.99-7.09(2H,m), 7.00(1H,s), 8.01(1H,s).

MS m/z: 371(M⁺+H).

Referential Example 47t-Butyl[5-chloro-4-[(2,5-difluorophenyl)(hydroxy)methyl]pyridin-2-yl]carbamate

Under a nitrogen atmosphere, a tetrahydrofuran solution (1M, 33.8 ml,33.8 mmol) of sodium bis(trimethylsilyl)amide was added to atetrahydrofuran (80 ml) solution of(2-amino-5-chloropyridin-4-yl)(2,5-difluorophenyl)methyl t-butylcarbonate (5.70 g, 15.4 mmol) at 0° C., followed by further addition ofa tetrahydrofuran (20 ml) solution of di-t-butyl dicarbonate (3.69 g,16.9 mmol). After stirring at room temperature for 30 minutes, asaturated aqueous solution of ammonium chloride was added to thereaction mixture. The product thus obtained was extracted withdichloromethane. The organic layer was dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure.

The residue thus obtained was dissolved in a mixed solvent oftetrahydrofuran (50 ml) and methanol (50 ml). To the resulting solutionwas added 1N sodium hydroxide (50 ml) at room temperature. The resultingmixture was stirred at 50° C. for 2 hours and concentrated under reducedpressure. The product thus obtained was extracted with dichloromethane.The residue was washed with an ethanol/hexane mixed solvent andcollected by filtration to afford the title compound (3.49 g, 9.41 mmol,61%) as a white solid. The filtrate was concentrated under reducedpressure. The residue thus obtained was washed with an ethanol/diethylether/hexane mixed solvent and collected by filtration to give the titlecompound (828 mg, 2.23 mmol, 15%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 1.54(9H,s), 2.69(1H,d,J=4.9 Hz), 6.32(1H,d,J=4.9Hz), 6.88-7.08(3H,m), 7.81(1H,s), 8.17(1H,s), 8.33(1H,s).

MS m/z: 371(M⁺+H).

Referential Example 48 O-EthylS-(4-chloro-3-methoxyphenyl)dithiocarbonate

In 1N hydrochloric acid (80 ml) was dissolved 4-chloro-3-methoxyaniline(2.77 g, 17.6 mmol). After dropwise addition of a water (10 ml) solutionof sodium nitrite (1.33 g, 19.3 mmol) to the resulting solution at 0°C., the reaction mixture was stirred at the same temperature for 30minutes. The temperature of the reaction mixture was raised to 60° C. Atthe same temperature, a water (30 ml) solution of potassium O-ethyldithiocarbonate (3.10 g, 19.3 mmol) was added dropwise to the reactionmixture. The temperature of the reaction mixture was raised to 90° C.After stirring for 1 hour, the reaction mixture was cooled to roomtemperature. A saturated aqueous solution of sodium bicarbonate wasadded to the reaction mixture. The product thus obtained was extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure and the residue thus obtained was subjected to flash silica gelcolumn chromatography. The fraction obtained from thehexane:dichloromethane=9:1 eluate was concentrated under reducedpressure to give the title compound (1.05 g, 4.00 mmol, 23%) as a yellowoil.

¹H-NMR(400 MHz,CDCl₃)δ: 1.35(3H,t,J=7.1 Hz), 3.91(3H,s), 4.62(2H,q,J=7.1Hz), 7.03-7.08(2H,m), 7.41(1H,d,J=8.1 Hz).

MS m/z: 263(M⁺+H).

Example 237t-Butyl[5-chloro-4-[(4-chloro-3-methoxyphenylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbamate

To an ethanol (5 ml) solution of O-ethyl S-(4-chloro-3-methoxyphenyl)dithiocarbonate (394 mg, 1.50 mmol) was added a 1N aqueous solution ofsodium hydroxide (5 ml). The resulting mixture was heated under refluxfor 1 hour. After the reaction mixture was cooled to room temperature,ethanol was distilled off under reduced pressure. The residue was washedwith dichloromethane. The water layer was acidified with acetic acid.The product thus obtained was extracted with dichloromethane. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure to give4-chloro-3-methoxybenzenethiol as a colorless oil.

To a dichloromethane solution of thet-butyl[5-chloro-4-[(2,5-difluorophenyl)(hydroxy)methyl]pyridin-2-yl]carbamate(371 mg, 1.00 mmol) obtained in Referential Example 47 were addedmethanesulfonyl chloride (0.155 ml, 2.00 mmol) and then, triethylamine(0.418 ml, 3.00 mmol) at 0° C. The resulting mixture was stirred at roomtemperature for 2 hours. The reaction mixture was washed with asaturated aqueous solution of sodium bicarbonate. The organic layer wasdried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure.

To an N,N-dimethylformamide (10 ml) solution of the residue weresequentially added an N,N-dimethylformamide (5 ml) solution of the4-chloro-3-methoxybenzenethiol obtained above and potassium carbonate(207 mg, 1.50 mmol) under a nitrogen atmosphere. The resulting mixturewas stirred at room temperature for 20 hours. Ethyl acetate was added tothe reaction mixture. The resulting mixture was washed with a saturatedaqueous solution of sodium bicarbonate. The organic layer was dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure. The residue thus obtained was subjected to flashsilica gel chromatography. The fraction obtained from the hexane:ethylacetate=19:1 eluate was concentrated under reduced pressure to give thetitle compound (354 mg, 0.67 mmol, 67%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 1.55(9H,s), 3.81(3H,s), 6.07(1H,s),6.91-7.08(3H,m), 6.97(1H,dd,J=7.8,2.0 Hz), 7.00(1H,d,J=2.0 Hz),7.23(1H,d,J=7.8 Hz), 7.86(1H,s), 8.18(1H,s), 8.55(1H,s).

MS m/z: 527(M⁺+H).

Example 238t-Butyl[5-chloro-4-[(4-chloro-3-methoxyphenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbamate

To an ethyl acetate (8 ml) solution oft-butyl[5-chloro-4-[(4-chloro-3-methoxyphenylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbamate(354 mg, 0.67 mmol) were added methanol (8 ml), 31% aqueous hydrogenperoxide (8 ml) and hexaammonium heptamolybdate tetrahydrate (166 mg,0.13 mmol). The resulting mixture was stirred at room temperature for 20hours. Water was added to the reaction mixture and ethyl acetate andmethanol were distilled off under reduced pressure. To the residue wasadded a saturated aqueous solution of sodium bicarbonate. The productthus obtained was extracted with dichloromethane. The organic layer wasdried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate=9:1 eluate was concentrated underreduced pressure. The residue thus obtained was washed with a diethylether/hexane mixed solvent and collected by filtration to give the titlecompound (308 mg, 0.55 mmol, 82%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 1.58(9H,s), 3.82(3H,s), 6.27(1H,s),6.94-7.09(2H,m), 7.24(1H,d,J=2.0 Hz), 7.36(1H,dd,J=8.3,2.0 Hz),7.46(1H,d,J=8.3 Hz), 7.56-7.62(2H,s), 8.18(1H,s), 8.89(1H,s).

MS m/z: 559(M⁺+H).

Example 239[5-Chloro-4-[(4-chloro-3-methoxyphenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine

To a dichloromethane (5 ml) solution oft-butyl[5-chloro-4-[(4-chloro-3-methoxyphenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbamate(300 mg, 0.54 mmol) was added trifluoroacetic acid (5 ml) at 0° C. Theresulting mixture was stirred at room temperature for 2 hours. Thereaction mixture was concentrated under reduced pressure. The residuethus obtained was dissolved in dichloromethane. The resulting solutionwas washed with a 1N aqueous sodium hydroxide solution. The organiclayer was dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure. The residue thusobtained was washed with diethyl ether and then collected by filtrationto give the title compound (208 mg, 0.45 mmol, 84%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 3.82(3H,s), 4.66(2H,s), 6.14(1H,s),6.91-6.98(1H,m), 7.02-7.09(1H,m), 7.09(1H,d,J=2.0 Hz),7.25(1H,dd,J=8.3,2.0 Hz), 7.34(1H,s), 7.46(1H,d,J=8.3 Hz),7.51-7.57(1H,s), 7.99(1H,s).

IR(ATR)cm⁻¹: 3151, 1645, 1595, 1481, 1414, 1390, 1325, 1254, 1140, 1055,1026.

mp: 198 to 200° C.

Elemental Analysis for C₁₉H₁₄Cl₂F₂N₂O₃S: Calculated: C, 49.69; H, 3.07;Cl, 15.44; F, 8.27; N, 6.10; S, 6.98. Found: C, 49.56; H, 3.03; Cl,15.29; F, 8.58; N, 6.08; S, 7.07.

MS m/z: 459(M⁺+H).

Example 240[5-Chloro-4-[(2,5-difluorophenyl)(4-methoxyphenylsulfonyl)methyl]pyridin-2-yl]amine

To a dichloromethane solution of thet-butyl[5-chloro-4-[(2,5-difluorophenyl)(hydroxy)methyl]pyridin-2-yl]carbamate(148 mg, 0.40 mmol) obtained in Referential Example 47 were addedmethanesulfonyl chloride (0.046 ml, 0.60 mmol) and then, triethylamine(0.167 ml, 1.20 mmol) at 0° C. The resulting mixture was stirred at roomtemperature for 16 hours. The reaction mixture was washed with asaturated aqueous solution of sodium bicarbonate. The organic layer wasdried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure.

To an N,N-dimethylformamide (4 ml) solution of the residue thus obtainedwere added 4-methoxybenzenethiol (56 mg, 0.40 mmol) and then potassiumcarbonate (66 mg, 0.48 mmol) under a nitrogen atmosphere. The resultingmixture was stirred at room temperature for 19 hours. Ethyl acetate wasadded to the reaction mixture. The resulting mixture was washed with asaturated aqueous solution of sodium bicarbonate. The organic layer wasdried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure.

To an ethyl acetate (8 ml) solution of the residue thus obtained wereadded methanol (8 ml), 31% aqueous hydrogen peroxide (4 ml) andhexaammonium heptamolybdate tetrahydrate (99 mg, 0.08 mmol). Theresulting mixture was stirred at room temperature for 20 hours. Waterwas added to the reaction mixture. Ethyl acetate and methanol weredistilled off under reduced pressure. To the residue was added asaturated aqueous solution of sodium bicarbonate. The product thusobtained was extracted with dichloromethane. The organic layer was driedover anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure.

To a dichloromethane (3 ml) solution of the residue thus obtained wasadded trifluoroacetic acid (3 ml) at 0° C. The resulting mixture wasstirred at room temperature for 2 hours. The reaction mixture wasconcentrated under reduced pressure. The residue was dissolved indichloromethane. The resulting solution was washed with a saturatedaqueous solution of sodium bicarbonate. The organic layer was dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=3:2 eluate was concentrated under reduced pressure.The residue was washed with a diethyl ether/hexane mixed solvent andthen collected by filtration to give the title compound (67 mg, 0.16mmol, 40%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 3.87(3H,s), 4.63(2H,s), 6.10(1H,s),6.87-6.94(1H,m), 6.90(2H,d,J=8.8 Hz), 6.98-7.06(1H,m), 7.31(1H,s),7.51-7.57(1H,m), 7.59(2H,d,J=8.8 Hz), 7.97(1H,s).

IR(ATR)cm⁻¹: 3469, 3294, 3172, 1630, 1593, 1491, 1419, 1327, 1261, 1244,1230, 1142, 1092.

mp: 153-155° C.

Elemental Analysis for C₁₉H₁₅ClF₂N₂O₃S: Calculated: C, 53.71; H, 3.56;Cl, 8.34; F, 8.94; N, 6.59; S, 7.55. Found: C, 53.53; H, 3.55; Cl, 8.34;F, 9.06; N, 6.31; S, 7.79.

MS m/z: 425(M⁺+H).

Example 241[5-Chloro-4-[(5-chloropyridin-2-ylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine

In a similar manner to Example 240, the title compound (74 mg, 0.17mmol, 43%) was obtained as a white solid by using thet-butyl[5-chloro-4-[(2,5-difluorophenyl)(hydroxy)methyl]pyridin-2-yl]carbamate(148 mg, 0.40 mmol) obtained in Referential Example 47 and the5-chloro-2-pyridinethiol (58 mg, 0.40 mmol) obtained in ReferentialExample 17.

¹H-NMR(400 MHz,CDCl₃)δ: 4.62(2H,s), 6.77(1H,s), 6.95-7.08(2H,m),7.28(1H,s), 7.40-7.47(1H,m), 7.82-7.84(2H,m), 8.00(1H,s),8.68-8.70(1H,m).

IR(ATR)cm⁻¹: 3427, 3317, 3199, 1635, 1491, 1477, 1327, 1238, 1163, 1113,1018.

mp: 187 to 189° C.

Elemental Analysis for C₁₇H₁₁Cl₂F₂N₃O₂S: Calculated: C, 47.46; H, 2.58;Cl, 16.48; F, 8.83; N, 9.77; S, 7.45. Found: C, 47.43; H, 2.64; Cl,16.52; F, 8.98; N, 9.69; S, 7.71.

MS m/z: 430(M⁺+H).

Example 242N-[5-Chloro-4-[(5-chloropyridin-2-ylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]methanesulfonamide

Under an argon atmosphere, a tetrahydrofuran solution (1M, 0.705 ml,0.71 mmol) of sodium bis(trimethylsilyl)amide was added to atetrahydrofuran (4 ml) solution of[5-chloro-4-[(5-chloropyridin-2-ylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine(92 mg, 0.21 mmol) at 0° C. The resulting mixture was stirred for 30minutes. To the reaction mixture was added methanesulfonyl chloride(0.055 ml, 0.71 mmol). At the same temperature, the resulting mixturewas stirred for 2 hours. The temperature of the reaction mixture wasthen raised to room temperature. To the reaction mixture was added asaturated aqueous solution of ammonium chloride. The product thusobtained was extracted with diethyl ether. The organic layer was driedover anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel column chromatography. The fractionobtained from the dichloromethane:ethyl acetate=19:1 eluate wasconcentrated under reduced pressure. The residue thus obtained waswashed with an ethanol/hexane mixed solvent and then, collected byfiltration to give the title compound (27 mg, 0.053 mmol, 25%) as awhite solid.

¹H-NMR(400 MHz,CDCl₃)δ: 3.32(3H,s), 6.86(1H,s), 6.98-7.09(2H,m),7.36-7.43(1H,m), 7.75(1H,s), 7.85(1H,dd,J=8.3,2.2 Hz), 7.90(1H,d,J=8.3Hz), 7.93(1H,s), 8.32(1H,s), 8.67(1H,d,J=2.2 Hz).

IR(ATR)cm⁻¹: 1603, 1568, 1493, 1389, 1329, 1240, 1144, 1109.

mp: 214 to 216° C.

Elemental Analysis for C₁₈H₁₃Cl₂F₂N₃O₄S₂: Calculated: C, 42.53; H, 2.58;Cl, 13.95; F, 7.47; N, 8.27; S, 12.62. Found: C, 42.56; H, 2.56; Cl,14.03; F, 7.54; N, 8.23; S, 12.58.

MS m/z: 508(M⁺+H).

Referential Example 49 5-Chlorothiophene-2-thiol

To an acetic acid (15 ml) solution of 5-chlorothiophene-2-sulfonylchloride (0.557 ml, 4.00 mmol) was added a 1N hydrochloric acid (3 ml)solution of tin (II) chloride (3.03 g, 16.0 mmol) at 75° C. The reactionmixture was cooled to room temperature, followed by the addition ofwater thereto. The product was extracted with dichloromethane. Theorganic layer was dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure. To the residue thusobtained was added toluene, followed by concentration under reducedpressure again. The residue thus obtained was washed with diethyl ether,and collected by filtration to give the title compound (98 mg, 0.65mmol, 16%) as a yellow solid. The filtrate was concentrated underreduced pressure. The residue thus obtained was washed with a mixedsolvent of diethyl ether/hexane and collected by filtration to give thetitle compound (118 mg, 0.78 mmol, 20%) as a yellow solid.

¹H-NMR(400 MHz,CDCl₃)δ: 6.81(1H,d,J=3.9 Hz), 6.85(1H,d,J=3.9 Hz).

Example 243[5-Chloro-4-[(5-chlorothiophen-2-ylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine

In a similar manner to Example 240, the title compound (96 mg, 0.22mmol, 55%) was obtained as a white solid by using thet-butyl[5-chloro-4-[(2,5-difluorophenyl)(hydroxy)methyl]pyridin-2-yl]carbamate(148 mg, 0.40 mmol) obtained in Referential Example 47 and5-chlorothiophene-2-thiol (90 mg, 0.60 mmol).

¹H-NMR(400 MHz,CDCl₃)δ: 4.66(2H,s), 6.25(1H,s), 6.93(1H,d,J=4.2 Hz),6.97-7.11(2H,m), 7.28(1H,s), 7.29(1H,d,J=4.2 Hz), 7.47-7.53(1H,m),8.02(1H,s).

IR(ATR)cm⁻¹: 3438, 3180, 1643, 1595, 1543, 1485, 1404, 1315, 1242, 1138,993.

mp: 170 to 171° C.

Elemental Analysis for C₁₆H₁₀Cl₂F₂N₂O₂S₂: Calculated: C, 44.15; H, 2.32;Cl, 16.29; F, 8.73; N, 6.44; S, 14.73. Found: C, 44.22; H, 2.41; Cl,16.00; F, 8.77; N, 6.46; S, 14.81.

MS m/z: 435(M⁺+H).

Example 244t-Butyl[5-chloro-4-[(6-chloropyridin-3-ylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbamate

In a similar manner to Example 237, the title compound (190 mg, 0.38mmol, 94%) was obtained as a white solid by using the O-ethylS-(6-chloropyridin-3-yl) dithiocarbonate (187 mg, 0.80 mmol) obtained inReferential Example 26 and thet-butyl[5-chloro-4-[(2,5-difluorophenyl)(hydroxy)methyl]pyridin-2-yl]carbamate(151 mg, 0.41 mmol) obtained in Referential Example 47.

¹H-NMR(400 MHz,CDCl₃)δ: 1.56(9H,s), 6.01(1H,s), 6.93-7.08(3H,m),7.22(1H,d,J=8.3 Hz), 7.42(1H,s), 7.71(1H,dd,J=8.3,2.5 Hz), 8.16(1H,s),8.37(1H,d,J=2.5 Hz), 8.50(1H,s).

MS m/z: 498(M⁺+H).

Example 245[5-Chloro-4-[(6-chloropyridin-3-ylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine

To a dichloromethane (5 ml) solution oft-butyl[5-chloro-4-[(6-chloropyridin-3-ylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbamate(187 mg, 0.38 mmol) was added 3-chloroperbenzoic acid (199 mg, 0.75mmol) at room temperature. The resulting mixture was stirred for 2hours. The reaction mixture was washed with a 1N aqueous sodiumhydroxide solution. The organic layer was dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure.

The residue thus obtained was dissolved in dichloromethane (3 ml). At 0°C., trifluoroacetic acid (3 ml) was added and the resulting mixture wasstirred at room temperature for 1 hour. The reaction mixture wasconcentrated under reduced pressure. The residue was dissolved indichloromethane. The resulting solution was washed with a 1N aqueoussolution of sodium hydroxide. The organic layer was dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated underreduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure.The residue thus obtained was washed with an ethanol/hexane mixedsolvent, and collected by filtration to give the title compound (90 mg,0.21 mmol, 55%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 4.68(2H,s), 6.15(1H,s), 6.93-7.00(1H,m),7.05-7.12(1H,m), 7.29(1H,s), 7.44(1H,d,J=8.3 Hz), 7.48-7.54(1H,m),7.91(1H,dd,J=8.3,2.4 Hz), 8.01(1H,s), 8.58(1H,d,J=2.4 Hz).

IR(ATR)cm⁻¹: 3342, 3167, 1495, 1479, 1331, 1240, 1161, 1115.

mp: 157 to 158° C.

Elemental Analysis for C₁₇H₁₁Cl₂F₂N₃O₂S: Calculated: C, 47.46; H, 2.58;Cl, 16.48; F, 8.83; N, 9.77; S, 7.45. Found: C, 47.24; H, 2.59; Cl,16.50; F, 8.80; N, 9.82; S, 7.61.

MS m/z: 430(M⁺+H).

Example 2464-[(2-Amino-5-chloropyridin-4-yl)(2,5-difluorophenyl)methylsulfonyl]benzonitrile

In a similar manner to Example 240, the title compound (99 mg, 0.24mmol, 59%) was obtained as a white solid by using thet-butyl[5-chloro-4-[(2,5-difluorophenyl)(hydroxy)methyl]pyridin-2-yl]carbamate(148 mg, 0.40 mmol) obtained in Referential Example 47 and4-mercaptobenzonitrile (56 mg, 0.41 mmol).

¹H-NMR(400 MHz,CDCl₃): 4.68(2H,s), 6.15(1H,s), 6.89-6.96(1H,m),7.03-7.10(1H,m), 7.31(1H,s), 7.49-7.55(1H,m), 7.76(2H,d,J=8.5 Hz),7.81(2H,d,J=8.5 Hz), 7.99(1H,s).

IR(ATR)cm¹: 3388, 1618, 1495, 1415, 1331, 1149.

mp: 233 to 235° C.

Elemental Analysis for C₁₉H₁₂ClF₂N₃O₂S: Calculated: C, 54.36; H, 2.88;Cl, 8.44; F, 9.05; N, 10.01; S, 7.64. Found: C, 54.41; H, 2.93; Cl,8.41; F, 8.92; N, 9.92; S, 7.69.

MS m/z: 420(M⁺+H).

Example 247[5-Chloro-4-[(2,5-difluorophenyl)(3,4-difluorophenylsulfonyl)methyl]pyridin-2-yl]amine

In a similar manner to Example 240, the title compound (59 mg, 0.14mmol, 27%) was obtained as a white solid by using thet-butyl[5-chloro-4-[(2,5-difluorophenyl)(hydroxy)methyl]pyridin-2-yl]carbamate(185 mg, 0.50 mmol) obtained in Referential Example 47 and3,4-difluorobenzenethiol (84 mg, 0.55 mmol).

¹H-NMR(400 MHz,CDCl₃)δ: 4.67(2H,s), 6.13(1H,s), 6.91-6.98(1H,m),7.03-7.10(1H,m), 7.23-7.31(1H,m), 7.31(1H,s), 7.45-7.55(3H,m),8.00(1H,s).

IR(ATR)cm⁻¹: 3452, 3168, 1635, 1599, 1493, 1415, 1325, 1281, 1244, 1144,1120.

mp: 140 to 141° C.

Elemental Analysis for C₁₈H₁₁ClF₄N₂O₂S: Calculated: C, 50.18; H, 2.57;Cl, 8.23; F, 17.64; N, 6.50; S, 7.44. Found: C, 50.12; H, 2.60; Cl,8.25; F, 17.35; N, 6.51; S, 7.58.

MS m/z: 431(M⁺+H).

Example 248N-[5-Chloro-4-[(2,5-difluorophenyl)(3,4-difluorophenylsulfonyl)methyl]pyridin-2-yl]-N-(methylsulfonyl)methanesulfonamide

Under a nitrogen atmosphere, methanesulfonyl chloride (0.034 ml, 0.44mmol), triethylamine (0.062 ml, 0.44 mmol) and 4-dimethylaminopyridine(4 mg, 0.03 mmol) were added to a dichloromethane (3 ml) solution of[5-chloro-4-[(2,5-difluorophenyl)(3,4-difluorophenylsulfonyl)methyl]pyridin-2-yl]amine(63 mg, 0.15 mmol) at 0° C. The resulting mixture was stirred at roomtemperature for 17 hours. The reaction mixture was washed with 1Nhydrochloric acid. The organic layer was dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure. The residue thus obtained was subjected to flash silica gelcolumn chromatography. The fraction obtained from the hexane:ethylacetate=3:1 eluate was concentrated under reduced pressure to give thetitle compound (73 mg, 0.12 mmol, 85%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 3.63(6H,s), 6.22(1H,s), 7.02-7.16(2H,m),7.22-7.31(1H,m), 7.45-7.51(2H,m), 7.56-7.62(1H,m), 8.17(1H,s),8.45(1H,s).

MS m/z: 587(M⁺+H).

Example 249N-[5-Chloro-4-[(2,5-difluorophenyl)(3,4-difluorophenylsulfonyl)methyl]pyridin-2-yl]methanesulfonamide

Under a nitrogen atmosphere, a tetrahydrofuran solution (1M, 0.147 ml,0.15 mmol) of tetrabutylammonium fluoride was added to a tetrahydrofuran(2 ml) solution ofN-[5-chloro-4-[(2,5-difluorophenyl)(3,4-difluorophenylsulfonyl)methyl]pyridin-2-yl]-N-(methylsulfonyl)methanesulfonamide(72 mg, 0.12 mmol). The resulting mixture was stirred at roomtemperature for 2 hours. After the reaction mixture was concentratedunder reduced pressure, the residue thus obtained was dissolved in ethylacetate. The resulting solution was washed sequentially with 1Nhydrochloric acid and a saturated aqueous solution of ammonium chloride.The organic layer was dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated under reduced pressure. The residue thusobtained was subjected to flash silica gel chromatography. The fractionobtained from the hexane:ethyl acetate=3:1 eluate was concentrated underreduced pressure. The residue thus obtained was washed with a mixedsolvent of diethyl ether/hexane and collected by filtration to give thetitle compound (53 mg, 0.10 mmol, 84%) as a white solid.

¹H-NMR(400 MH,CDCl₃)δ: 3.35(3H,s), 6.19(1H,s), 6.92-6.99(1H,m),7.04-7.12(1H,m), 7.25-7.32(1H,m), 7.44-7.60(3H,m), 7.98(1H,s),7.99(1H,s), 8.34(1H,s).

IR(ATR)cm⁻¹: 1599, 1495, 1468, 1333, 1281, 1146, 1003, 970.

mp: 118 to 120° C.

MS m/z: 509(M⁺+H).

FAB-MS: 509.0044 (Calcd for Cl₉H₁₄ClF₄N₂O₄S₂: 509.0020).

Referential Example 50 O-Ethyl S-(6-trifluoromethylpyridin-3-yl)dithiocarbonate

After 6-trifluoromethylpyridin-3-ylamine (1.00 g, 6.02 mmol) wasdissolved in 1N hydrochloric acid (15 ml) and methanol (3 ml), a water(3 ml) solution of sodium nitrite (506 mg, 7.22 mmol) was added dropwiseto the resulting solution at −10° C. The reaction mixture was addeddropwise to a water (15 ml) solution of potassium o-ethyldithiocarbonate (1.93 g, 12.0 mmol) heated to 65° C. At the sametemperature, the reaction mixture was stirred for 30 minutes. After thereaction mixture was cooled to room temperature, the product thusobtained was extracted with ethyl acetate. The extract was washed withbrine. The organic layer was dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure. Theresidue thus obtained was subjected to flash silica gel columnchromatography. The fraction obtained from the hexane:ethylacetate=100:1 eluate was concentrated under reduced pressure to give thetitle compound (895 mg, 3.35 mmol, 56%) as a yellow oil.

¹H-NMR(400 MHz,CDCl₃)δ: 1.38(3H,t,J=7.1 Hz), 4.65(2H,q,J=7.1 Hz),7.76(1H,d,J=8.1 Hz), 8.01(1H,dd,J=8.1,2.0 Hz), 8.79(1H,d,J=2.0 Hz).

MS m/z: 268(M⁺+H).

Example 250[5-Chloro-4-[(2,5-difluorophenyl)(6-trifluoromethylpyridin-3-ylsulfonyl)methyl]pyridin-2-yl]amine

To an ethanol (2 ml) solution of O-ethylS-(6-trifluoromethylpyridin-3-yl) dithiocarbonate (160 mg, 0.60 mmol)was added a 1N aqueous sodium hydroxide solution (2 ml). The resultingmixture was stirred at 65° C. for 2 hours. After the reaction mixturewas cooled to room temperature and then, water was added thereto. Theresulting mixture was washed with dichloromethane. The water layer wasacidified with 1N hydrochloric acid, and the product was extracted withdichloromethane. The organic layer was dried over anhydrous sodiumsulfate and then filtered. The filtrate was concentrated under reducedpressure to afford 6-trifluoromethylpyridine-3-thiol as a colorless oil.

To a dichloromethane solution of thet-butyl[5-chloro-4-[(2,5-difluorophenyl)(hydroxy)methyl]pyridin-2-yl]carbamate(185 mg, 0.50 mmol) obtained in Referential Example 47 were sequentiallyadded methanesulfonyl chloride (0.077 ml, 1.00 mmol) and triethylamine(0.279 ml, 2.00 mmol) at room temperature. The resulting mixture wasstirred at room temperature for 1 hour. The reaction mixture was washedwith a saturated aqueous solution of sodium bicarbonate. The organiclayer was dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure.

To an N,N-dimethylformamide (5 ml) solution of the residue thus obtainedwere added an N,N-dimethylformamide (5 ml) solution of the6-trifluoromethylpyridine-3-thiol obtained above and potassium carbonate(104 mg, 0.75 mmol) sequentially under a nitrogen atmosphere. Theresulting mixture was stirred at room temperature for 15 hours. Ethylacetate was added to the reaction mixture. The resulting mixture waswashed sequentially with a saturated aqueous solution of sodiumbicarbonate and brine. The organic layer was dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure.

To an ethyl acetate (10 ml) solution of the residue thus obtained wereadded methanol (10 ml), 31% aqueous hydrogen peroxide (5 ml) andhexaammonium heptamolybdate tetrahydrate (99 mg, 0.08 mmol). Theresulting mixture was stirred at 50° C. for 4 hours. To the reactionmixture was added water and ethyl acetate and methanol were distilledoff under reduced pressure. A saturated aqueous solution of sodiumbicarbonate was added to the residue. The product thus obtained wasextracted with dichloromethane. The organic layer was dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=9:1 eluate was concentrated under reduced pressure.

To a dichloromethane (5 ml) solution of the residue thus obtained wasadded trifluoroacetic acid (5 ml) at 0° C. The resulting mixture wasstirred at room temperature for 2 hours. After the reaction mixture wasconcentrated under reduced pressure, the residue was dissolved indichloromethane. The resulting solution was washed with a saturatedaqueous solution of sodium bicarbonate. The organic layer was dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure.The residue thus obtained was washed with an ethanol/hexane mixedsolvent and collected by filtration to give the title compound (75 mg,0.16 mmol, 32%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 4.71(2H,s), 6.18(1H,s), 6.91-6.99(1H,m),7.06-7.14(1H,m), 7.30(1H,s), 7.50-7.56(1H,m), 7.81(1H,d,J=8.1 Hz),8.01(1H,s), 8.20(1H,dd,J=8.1,2.0 Hz), 8.90 (1H,d,J=2.0 Hz).

IR(ATR)cm⁻¹: 3446, 3157, 1649, 1601, 1485, 1419, 1325, 1147, 1101, 1076.

mp: 201 to 202° C.

Elemental Analysis for C₁₈H₁₁ClF₅N₃O₂S.0.25H₂O: Calculated: C, 46.16; H,2.48; Cl, 7.57; F, 20.28; N, 8.97; S, 6.85. Found: C, 46.30; H, 2.36;Cl, 7.61; F, 19.96; N, 8.93; S, 7.12.

MS m/z: 464(M⁺+H).

Referential Example 51 O-Ethyl S-(4-chloro-3-fluorophenyl)dithiocarbonate

In a similar manner to Referential Example 50, the title compound (379mg, 1.51 mmol, 38%) was obtained as a yellow oil by using4-chloro-3-fluoroaniline (582 mg, 4.00 mmol).

¹H-NMR(400 MHz,CDCl₃)δ: 1.36(3H,t,J=7.1 Hz), 4.63(2H,q,J=7.1 Hz),7.22-7.25(1H,m), 7.30-7.35(1H,m), 7.43-7.49(1H,m).

Example 251[5-Chloro-4-[(4-chloro-3-fluorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine

In a similar manner to Example 250, the title compound (78 mg, 0.17mmol, 35%) was obtained as a white solid by using O-ethylS-(4-chloro-3-fluorophenyl) dithiocarbonate (150 mg, 0.60 mmol) and thet-butyl[5-chloro-4-[(2,5-difluorophenyl)(hydroxy)methyl]pyridin-2-yl]carbamate(185 mg, 0.50 mmol) obtained in Referential Example 47.

¹H-NMR(400 MHz,CDCl₃)δ: 4.68(2H,s), 6.14(1H,s), 6.92-6.99(1H,m),7.03-7.10(1H,m), 7.31(1H,s), 7.40-7.55(4H,m), 8.00(1H,s).

IR(ATR)cm⁻¹: 3159, 1628, 1543, 1495, 1473, 1408, 1335, 1238, 1149, 1055.

mp: 159 to 160° C.

Elemental Analysis for C₁₈H₁₁Cl₂F₃N₂O₂S: Calculated: C, 48.34; H, 2.48;Cl, 15.85; F, 12.74; N, 6.26; S, 7.17. Found: C, 48.22; H, 2.47; Cl,15.89; F, 12.75; N, 6.24; S, 7.34.

MS m/z: 447(M⁺+H).

Example 252 Methyl(E)-3-[4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropyridin-2-yl]acrylate

Under an argon atmosphere, methyl (triphenylphosphoranylidene)acetate(259 mg, 0.775 mmol) was added to a tetrahydrofuran (5 ml) solution ofthe[4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropyridin-2-yl]carbaldehyde(300 mg, 0.705 mmol) obtained in Example 200. The resulting mixture wasstirred at room temperature for 6 hours. The reaction mixture wasconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate=4:1 eluate was concentrated underreduced pressure to give the title compound (303 mg, 0.629 mmol, 89%) asa colorless amorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 3.84(3H,s), 6.07(1H,s), 6.92(1H,d,J=15.6 Hz),6.94-6.99(1H,m), 7.05-7.11(1H,m), 7.45(2H,d,J=8.3 Hz), 7.63(2H,d,J=8.3Hz), 7.65-7.69(1H,m), 7.73(1H,d,J=15.6 Hz), 8.05(1H,d,J=5.6 Hz),8.44(1H,s).

MS m/z: 482(M⁺+H).

Example 253 Methyl3-[4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropyridin-2-yl]propionate

A Raney nickel suspension (“R-100”, product of Nikko Rika Corporation)was washed sequentially with water and ethanol to give a correspondingethanol suspension. The resulting ethanol suspension (1 ml) was added toa solution of methyl(E)-3-[4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropyridin-2-yl]acrylate(290 mg, 0.602 mmol) in a mixture of ethanol (6 ml) and 1,4-dioxane (4ml). The resulting mixture was stirred vigorously for 30 minutes under ahydrogen atmosphere of 1 atmospheric pressure. The reaction mixture wasfiltered, followed by concentration under reduced pressure. The residuethus obtained was dissolved in dichloromethane. The resulting solutionwas dried over magnesium sulfate and concentrated under reducedpressure. The residue thus obtained was washed with hexane to give thetitle compound (252 mg, 0.521 mmol, 87%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 2.83(2H,t,J=7.1 Hz), 3.19(2H,t,J=7.1 Hz),3.71(3H,s), 6.06(1H,s), 6.93-6.99(1H,m), 7.03-7.09(1H,m),7.44(2H,d,J=8.6 Hz), 7.63(2H,d,J=8.6 Hz), 7.64-7.69(1H,m),7.88(1H,d,J=5.4 Hz), 8.31(1H,s).

MS m/z: 484(M⁺+H).

Example 2543-[4-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropyridin-2-yl]propionicacid

To a solution of methyl3-[4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropyridin-2-yl]propionate(150 mg, 0.310 mmol) in a mixture of methanol (2 ml) and tetrahydrofuran(2 ml) was added a 1N aqueous sodium hydroxide solution. The resultingmixture was stirred at room temperature for 10 minutes. The reactionmixture was made weakly acidic by the addition of 1N hydrochloric acid,followed by extraction with dichloromethane. The organic layer was driedover magnesium sulfate and concentrated under reduced pressure to givethe title compound (145 mg, 0.310 mmol, quant.) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 2.88(2H,t,J=6.6 Hz), 3.21-3.25(2H,m),6.07(1H,s), 6.93-6.99(1H,m), 7.04-7.10(1H,m), 7.45(2H,d,J=8.6 Hz),7.62(2H,d,J=8.6 Hz), 7.63-7.67(1H,m), 7.92(1H,d,J=5.4 Hz), 8.33(1H,s).

IR(ATR)cm⁻¹: 3453, 1716, 1664, 1614, 1571, 1496, 1430, 1394, 1330, 1284,1238, 1187, 1151, 1089, 1010.

mp: 89 to 91° C.

MS m/z: 470(M⁺+H).

Elemental Analysis for C₂₁H₁₅ClF₃NO₄S.0.75H₂O: Calculated: C, 52.18; H,3.44; Cl, 7.33; F, 11.79; N, 2.90; S, 6.63. Found: C, 52.20; H, 3.65;Cl, 7.11; F, 11.43; N, 2.99; S, 6.58.

Referential Example 522-Bromo-5-chloro-4-[(2,5-difluorophenyl)hydroxymethyl]pyridine

Under an argon atmosphere, n-butyl lithium (a 1.58M hexane solution, 88ml, 138 mmol) was added to a tetrahydrofuran (200 ml) solution ofdiisopropylamine (21 ml, 150 mmol) at −78° C. The resulting mixture wasstirred for 1 hour. To the reaction mixture was added dropwise atetrahydrofuran (100 ml) solution of 2-bromo-5-chloropyridine (19 g,98.7 mmol). The resulting mixture was stirred for 1.5 hours. To thereaction mixture was added dropwise 2,5-difluorobenzaldehyde (16 ml, 148mmol), followed by stirring for 2 hours. After addition of water, theresulting mixture was concentrated under reduced pressure. The residuewas extracted with dichloromethane. The organic layer thus obtained wasdried over magnesium sulfate, and concentrated under reduced pressure.The residue thus obtained was subjected to silica gel columnchromatography. The fraction obtained from the hexane:ethyl acetate=6:1eluate was concentrated under reduced pressure to give the titlecompound (24.8 g, 74.1 mmol, 75%) as a pale yellow powder.

¹H-NMR(400 MHz,CDCl₃)δ: 2.65(1H,d,J=4.2 Hz), 6.20(1H,d,J=4.2 Hz),6.88-6.92(1H,m), 7.01-7.27(2H,m), 7.81(1H,s), 8.30(1H,s).

MS m/z: 334(M⁺+H).

Example 2552-Bromo-5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine

Under an argon atmosphere, triethylamine (2.6 ml, 18.5 mmol) andmethanesulfonyl chloride (1.3 ml, 16.0 mmol) were added to adichloromethane solution (80 ml) of2-bromo-5-chloro-4-[(2,5-difluorophenyl)hydroxymethyl]pyridine (4.12 g,12.3 mmol) under ice cooling. The resulting mixture was stirred at roomtemperature for 1.5 hours. To the reaction mixture was added a saturatedaqueous solution of sodium bicarbonate, followed by extraction withdiethyl ether. The extract was washed with brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure.

To a dimethylformamide (40 ml) solution of the residue thus obtainedwere added 4-chlorobenzenethiol (2.1 g, 14.8 mmol) and potassiumcarbonate (2.6 g, 18.5 mmol). The resulting mixture was stirred at 50°C. for 4 hours. After cooling to room temperature, the reaction mixturewas diluted with diethyl ether. The diluted mixture was washedsequentially with water and brine. The organic layer thus obtained wasdried over magnesium sulfate, and concentrated under reduced pressure.The residue thus obtained was subjected to flash silica gel columnchromatography. The fraction obtained from the hexane:ethyl acetate=10:1eluate was concentrated under reduced pressure to give the titlecompound (3.3 g, 7.16 mmol, 58%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 5.96(1H,s), 6.99-7.06(2H,m), 7.15-7.20(1H,m),7.25(2H,d,J=8.8 Hz), 7.28(2H,d,J=8.8 Hz), 7.69(1H,s), 8.32(1H,s).

MS m/z: 460(M⁺+H).

Example 256[5-Chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]methanol

Under an argon atmosphere, n-butyl lithium (a 1.58M hexane solution,0.33 ml, 0.520 mmol) was added to a toluene (5 ml) solution of2-bromo-5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine(200 mg, 0.434 mmol) at −78° C. The resulting mixture was stirred for 2hours. To the reaction mixture was added dropwise dimethylformamide (44μl, 0.564 mmol). The reaction mixture was stirred for 1 hour. To thereaction mixture were added methanol (5 ml) and sodium borohydride (33mg, 0.868 mmol). The temperature of the resulting mixture was raised toroom temperature, followed by stirring for 2 hours. Water was added tothe reaction mixture and then, the resulting mixture was extracted withethyl acetate. The extract was washed with brine. The organic layer thusobtained was dried over magnesium sulfate, and concentrated underreduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=2:1 eluate was concentrated under reduced pressureto give the title compound (142 mg, 0.344 mmol, 80%) as a colorlessamorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 3.19(1H,t,J=5.4 Hz), 4.75(2H,d,J=5.4 Hz),6.06(1H,s), 6.96-7.04(2H,m), 7.16-7.21(1H,m), 7.22(2H,d,J=8.8 Hz),7.25(2H,d,J=8.8 Hz), 7.52(1H,s), 8.51(1H,s).

MS m/z: 412(M⁺+H).

Example 257[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]methanol

To a methanol (5 ml) solution of[5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]methanol(130 mg, 0.315 mmol) were added hexaammonium heptamolybdate tetrahydrate(20 mg) and 30% aqueous hydrogen peroxide (3 ml). The resulting mixturewas stirred for 6 hours. After water was added to the reaction mixture,the resulting mixture was extracted with ethyl acetate. The extract waswashed sequentially with water, a saturated aqueous solution of sodiumbicarbonate, a saturated aqueous solution of sodium thiosulfate andbrine. The organic layer thus obtained was dried over magnesium sulfate,and concentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate=2:1 eluate was concentrated underreduced pressure. The residue was recrystallized from hexane:ethylacetate to give the title compound (101 mg, 0.227 mmol, 72%) as a whitepowder.

¹H-NMR(400 MHz,CDCl₃)δ: 3.22(1H,t,J=5.4 Hz), 4.86(2H,dd,J=5.4,2.0 Hz),6.24(1H,s), 6.91-6.97(1H,m), 7.02-7.09(1H,m), 7.45(2H,d,J=8.8 Hz),7.52-7.57(1H,m), 7.61(2H,d,J=8.8 Hz), 8.10(1H,s), 8.52(1H,s).

IR(ATR)cm⁻¹: 3255, 1583, 1492, 1428, 1394, 1330, 1280, 1236, 1159, 1085,1035.

mp: 164 to 165° C.

MS m/z: 444(M⁺+H).

Elemental Analysis for C₁₉H₁₃Cl₂F₂NO₃S: Calculated: C, 51.36; H, 2.95;Cl, 15.96; F, 8.55; N, 3.15; S, 7.22. Found: C, 51.26; H, 2.91; Cl,15.97; F, 8.72; N, 3.11; S, 7.45.

Example 258[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbaldehyde

Under a nitrogen atmosphere, dimethyl sulfoxide (880 μl, 11.3 mmol),triethylamine (1.14 ml, 11.3 mmol) and sulfur trioxide pyridine complex(1.07 g, 6.75 mmol) were added to a dichloromethane (25 ml) solution of[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]methanol(1.0 g, 2.25 mmol). The resulting mixture was stirred at roomtemperature for 18 hours. The reaction mixture was concentrated underreduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=2:1 eluate was concentrated under reduced pressureto give the title compound (770 mg, 1.74 mmol, 77%) as a colorlessamorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 6.23(1H,s), 6.93-6.99(1H,m), 7.04-7.10(1H,m),7.44(2H,d,J=8.8 Hz), 7.59-7.64(1H,m), 7.62(2H,d,J=8.8 Hz), 8.69(1H,s),8.73(1H,s), 10.09(1H,s).

MS m/z: 442(M⁺+H).

Example 259 Methyl(E)-3-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]acrylate

Under an argon atmosphere, methyl (triphenylphosphoranylidene)acetate(632 mg, 1.89 mmol) was added to a tetrahydrofuran (15 ml) solution of[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbaldehyde(760 mg, 1.72 mmol). The resulting mixture was stirred at roomtemperature for 3 hours. The reaction mixture was concentrated underreduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=4:1 eluate was concentrated under reduced pressureto give the title compound (776 mg, 1.56 mmol, 91%) as a colorlessamorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 3.85(3H,s), 6.22(1H,s), 6.93-6.98(1H,m),6.99(1H,d,J=15.6 Hz), 7.03-7.10(1H,m), 7.44(2H,d,J=8.6 Hz),7.54-7.58(1H,m), 7.60(2H,d,J=8.6 Hz), 7.73(1H,d,J=15.6 Hz), 8.17(1H,s),8.56(1H,s).

MS m/z: 498(M⁺+H).

Example 260 Methyl3-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]propionate

A Raney nickel suspension (“R-100”, product of Nikko Rika Corporation)was washed sequentially with water and ethanol to give a correspondingethanol suspension. The resulting ethanol suspension (2 ml) was added toa solution of methyl(E)-3-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]acrylate(770 mg, 1.55 mmol) in a mixture of ethanol (10 ml) and 1,4-dioxane (5ml). Under a hydrogen atmosphere of 1 atmospheric pressure, theresulting mixture was stirred vigorously for 30 minutes. After thereaction mixture was filtered, the filtrate was concentrated underreduced pressure. The residue thus obtained was dissolved indichloromethane (15 ml). The resulting solution was dried over magnesiumsulfate, and concentrated under reduced pressure to give the titlecompound (720 mg, 1.44 mmol, 93%) as a white powder.

¹H-NMR(400 MHZ,CDCl₃)δ: 2.84(2H,t,J=7.1 Hz), 3.20(2H,t,J=7.1 Hz),3.70(3H,s), 6.22(1H,s), 6.92-6.97(1H,m), 7.02-7.08(1H,m),7.43(2H,d,J=8.6 Hz), 7.53-7.58(1H,m), 7.61(2H,d,J=8.6 Hz), 8.03(1H,s),8.44(1H,s).

MS m/z: 500(M⁺+H).

Example 2613-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]propionicacid

To a solution of methyl3-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]propionate(200 mg, 0.400 mmol) in a mixture of methanol (2 ml) and tetrahydrofuran(2 ml) was added a 1N aqueous sodium hydroxide solution (2 ml). Theresulting mixture was stirred at room temperature for 1 hour. Thereaction mixture was made weakly acidic by the addition of 1Nhydrochloric acid, followed by extraction with dichloromethane. Theorganic layer was dried over magnesium sulfate, and concentrated underreduced pressure. The residue thus obtained was recrystallized fromhexane:ethyl acetate to give the title compound (161 mg, 0.331 mmol,83%) as a white powder.

¹H-NMR(400 MHz,CDCl₃): 2.90(2H,t,J=6.7 Hz), 3.24(2H,t,J=6.7 Hz),6.21(1H,s), 6.92-6.97(1H,m), 7.03-7.08(1H,m), 7.44(2H,d,J=8.6 Hz),7.51-7.56(1H,m), 7.61(2H,d,J=8.6 Hz), 8.06(1H,s), 8.47(1H,s).

IR(ATR)cm⁻¹: 1718, 1587, 1496, 1423, 1396, 1365, 1321, 1280, 1240, 1205,1174, 1083, 1054, 1014.

mp: 194 to 196° C.

MS m/z: 486(M⁺+H).

Elemental Analysis for C₂₁H₁₅Cl₂F₂NO₄S: Calculated: C, 51.86; H, 3.11;Cl, 14.58; F, 7.81; N, 2.88; S, 6.59. Found: C, 51.87; H, 3.07; Cl,14.37; F, 7.77; N, 2.95; S, 6.75.

Example 2625-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]picolinicacid

To a formic acid (3 ml) solution of the[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbaldehyde(150 mg, 0.339 mmol) obtained in Example 258 was added 30% aqueoushydrogen peroxide (115 μl, 1,02 mmol). The resulting mixture was stirredat room temperature for 3 hours. Water was added to the reaction mixtureand the solid thus precipitated was filtered. The solid was washed withwater. The resulting solid was dissolved in ethyl acetate. The resultingsolution was washed sequentially with water and brine. The organic layerthus obtained was dried over magnesium sulfate, and concentrated underreduced pressure. The residue thus obtained was recrystallized fromhexane:ethyl acetate to give the title compound (88 mg, 0.192 mmol, 57%)as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 6.30(1H,s), 6.93-7.00(1H,m), 7.05-7.11(1H,m),7.45(2H,d,J=8.8 Hz), 7.62-7.66(1H,m), 7.64(2H,d,J=8.8 Hz), 8.95(1H,s),9.24(1H,s).

IR(ATR)cm⁻¹: 1758, 1712, 1583, 1542, 1494, 1425, 1396, 1328, 1280, 1228,1153, 1085, 1054, 1014.

mp: 94 to 96° C.

MS m/z: 458 (M⁺+H).

Elemental Analysis for C₁₉H₁₁Cl₂F₂NO₄S: Calculated: C, 49.80; H, 2.42;Cl, 15.47; F, 8.29; N, 3.06; S, 7.00. Found: C, 50.05; H, 2.58; Cl,15.17; F, 8.28; N, 3.06; S, 7.05.

Example 2632-Bromo-5-chloro-4-[(2,5-difluorophenyl)(4-trifluoromethylphenylthio)methyl]pyridine

To a dichloromethane solution of the2-bromo-5-chloro-4-[(2,5-difluorophenyl)hydroxymethyl]pyridine (1.34 g,4.00 mmol) obtained in Referential Example 52 were sequentially addedmethanesulfonyl chloride (0.619 ml, 8.00 mmol) and triethylamine (2.23ml, 16.0 mmol) under a nitrogen atmosphere. The resulting mixture wasstirred at room temperature for 1 hour. The reaction mixture was washedsequentially with water and brine. The organic layer was dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure.

To an N,N-dimethylformamide (60 ml) solution of the resulting residuewere sequentially added 4-trifluorobenzenethiol (784 mg, 4.40 mmol) andpotassium carbonate (663 mg, 4.80 mmol) under a nitrogen atmosphere. Theresulting mixture was stirred at room temperature for 17 hours. Ethylacetate was added to the reaction mixture and the resulting mixture waswashed with a saturated aqueous solution of sodium bicarbonate. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure. The residue thusobtained was subjected to flash silica gel chromatography. The fractionobtained from the hexane:ethyl acetate=50:1 eluate was concentratedunder reduced pressure to give the title compound (1.33 g, 2.69 mmol,67%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 6.10(1H,s), 6.99-7.11(2H,m), 7.14-7.20(1H,m),7.36(2H,d,J=8.1 Hz), 7.52(2H,d,J=8.1 Hz), 7.69(1H,s), 8.36(1H,s).

MS m/z: 494,496(M⁺+H)

Example 264 Methyl(E)-3-[5-chloro-4-[(2,5-difluorophenyl)(4-trifluoromethylphenylthio)methyl]pyridin-2-yl]acrylate

To a toluene (12 ml) solution of2-bromo-5-chloro-4-[(2,5-difluorophenyl)(4-trifluoromethylphenylthio)methyl]pyridine(396 mg, 0.80 mmol) was added a hexane solution (1.59M, 0.604 ml, 0.96mmol) of n-butyl lithium at −78° C. under an argon atmosphere. Theresulting mixture was stirred for 30 minutes. At the same temperature,N,N-dimethylformamide (0.081 ml, 1.04 mmol) was added and the resultingmixture was stirred for 30 minutes. To the reaction mixture were added asaturated aqueous solution of ammonium chloride and then water. Afterthe temperature of the resulting mixture was raised to room temperature,the product thus obtained was extracted with diethyl ether. The organiclayer was dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel chromatography. The fraction obtained fromthe hexane:ethyl acetate=9:1 eluate was concentrated under reducedpressure to give an aldehyde compound (186 mg).

The aldehyde compound (133 mg) was dissolved in tetrahydrofuran (2 ml).To the resulting solution was addedmethyl(triphenylphosphoranylidene)acetate (120 mg, 0.36 mmol) at roomtemperature. The resulting mixture was stirred at the same temperaturefor 18 hours. After the reaction mixture was concentrated under reducedpressure, the residue thus obtained was subjected to flash silica gelchromatography. The fraction obtained from the hexane:ethyl acetate=19:1eluate was concentrated under reduced pressure to give the titlecompound (132 mg, 0.26 mmol, 46%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 3.82(3H,s), 6.17(1H,s), 6.92(1H,d,J=15.7 Hz),6.99-7.09(2H,m), 7.13-7.18(1H,m), 7.35(2H,d,J=8.1 Hz), 7.50(2H,d,J=8.1Hz), 7.61(1H,s), 7.61(1H,d,J=15.7 Hz), 8.59(1H,s).

MS m/z: 500(M⁺+H).

Example 265 Methyl(E)-3-[5-chloro-4-[(2,5-difluorophenyl)(4-trifluoromethylphenylsulfonyl)methyl]pyridin-2-yl]acrylate

To an ethyl acetate (6 ml) solution of methyl(E)-3-[5-chloro-4-[(2,5-difluorophenyl)(4-trifluoromethylphenylthio)methyl]pyridin-2-yl]acrylate(118 mg, 0.24 mmol) were added methanol (6 ml), 31% aqueous hydrogenperoxide (6 ml) and hexaammonium heptamolybdate tetrahydrate (58 mg,0.05 mmol). The resulting mixture was stirred at room temperature for 11hours. To the reaction mixture was added water. After ethyl acetate andmethanol were distilled off under reduced pressure, brine was added tothe residue. The product thus obtained was extracted with ethyl acetate.The organic layer was dried over anhydrous sodium sulfate, and filtered.The filtrate was concentrated under reduced pressure. The residue thusobtained was subjected to flash silica gel column chromatography. Thefraction obtained from the hexane:ethyl acetate=9:1 eluate wasconcentrated under reduced pressure to give the title compound (111 mg,0.21 mmol, 88%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 3.86(3H,s), 6.25(1H,s), 6.91-6.98(1H,m),7.01(1H,d,J=15.7 Hz), 7.04-7.11(1H,m), 7.53-7.59(1H,m), 7.74(1H,d,J=15.7Hz), 7.74(2H,d,J=8.3 Hz), 7.83(2H,d,J=8.3 Hz), 8.18(1H,s), 8.56(1H,s).

MS m/z: 532(M⁺+H).

Example 266 Methyl3-[5-chloro-4-[(2,5-difluorophenyl)(4-trifluoromethylphenylsulfonyl)methyl]pyridin-2-yl]propionate

In a mixed solvent of ethyl acetate (3 ml) and methanol (3 ml) wasdissolved methyl(E)-3-[5-chloro-4-[(2,5-difluorophenyl)(4-trifluoromethylphenylsulfonyl)methyl]pyridin-2-yl]acrylate(110 mg, 0.21 mmol). To the resulting solution was added 10%palladium-carbon catalyst (60 mg). Under a hydrogen atmosphere, theresulting mixture was stirred at room temperature for 2 hours. After thecatalyst was removed by Celite filtration, the filtrate was concentratedunder reduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=4:1 eluate was concentrated under reduced pressureto give the title compound (94 mg, 0.18 mmol, 85%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 2.82-2.89(2H,m), 3.21(2H,t,J=7.1 Hz),3.70(3H,s), 6.25(1H,s), 6.90-6.97(1H,m), 7.03-7.10(1H,m),7.54-7.60(1H,m), 7.73(2H,d,J=8.3 Hz), 7.84(2H,d,J=8.3 Hz), 8.04(1H,s),8.44(1H,s).

MS m/z: 534(M⁺+H)

Example 2673-[5-Chloro-4-[(2,5-difluorophenyl)(4-trifluoromethylphenylsulfonyl)methyl]pyridin-2-yl]propionicacid

To a tetrahydrofuran (2 ml) solution of methyl3-[5-chloro-4-[(2,5-difluorophenyl)(4-trifluoromethylphenylsulfonyl)methyl]pyridin-2-yl]propionate(92 mg, 0.17 mmol) were added methanol (2 ml) and a 1N aqueous solutionof sodium hydroxide (2 ml) at 0° C. The resulting mixture was stirred atroom temperature for 2 hours. To the reaction mixture was added 1Nhydrochloric acid and the product thus obtained was extracted withdichloromethane. The organic layer was dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure. The residue thus obtained was washed with ethanol andcollected by filtration to give the title compound (61 mg, 0.12 mmol,68%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 2.90(2H,t,J=6.7 Hz), 3.18-3.31(2H,m),6.25(1H,s), 6.90-6.97(1H,m), 7.03-7.10(1H,m), 7.51-7.57(1H,m),7.74(2H,d,J=8.3 Hz), 7.82(2H,d,J=8.3 Hz), 8.07(1H,s), 8.47(1H,s).

IR(ATR)cm⁻¹: 1707, 1495, 1408, 1321, 1244, 1174, 1159, 1124, 1063.

mp: 166 to 167° C.

Elemental Analysis for C₂₂H₁₅ClF₅NO₄S: Calculated: C, 50.83; H, 2.91;Cl, 6.82; F, 18.27; N, 2.69; S, 6.17. Found: C, 50.66; H, 2.93; Cl,6.87; F, 17.83; N, 2.75; S, 6.28.

MS m/z: 520(M⁺+H).

Example 268N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]-1-methyl-1H-imidazole-4-sulfonamide

To a methylene chloride (5 ml) solution of the[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine(93 mg, 0.217 mmol) obtained in Example 196 and pyridine (21 μl, 0.260mmol) was added 1-methyl-1H-imidazole-4-sulfonyl chloride (47 mg, 0.260mmol). The resulting mixture was stirred at room temperature for 18hours. After pyridine (1 ml) was added to the reaction mixture and theresulting mixture was stirred at room temperature for 7 hours, thereaction mixture was concentrated under reduced pressure. To the residuethus obtained was added ethyl acetate. The resulting mixture was washedsequentially with a saturated aqueous solution of sodium bicarbonate andbrine, dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated under reduced pressure. The residue thus obtained wassubjected to silica gel column chromatography. The fraction obtainedfrom the methanol:methylene chloride (=1:50) eluate was concentratedunder reduced pressure to yield a white solid. The resulting white solidwas washed with ethanol, and collected by filtration to give the titlecompound (68 mg, 0.119 mmol, 55%) as a white powder.

¹H-NMR(400 MHz,DMSO-d₆)δ: 3.69(3H,s), 6.25(1H,s), 7.29-7.45(2H,m),7.47-7.54(1H,m), 7.68(2H,d,J=8.8 Hz), 7.75(2H,d,J=8.8 Hz), 7.77(1H,s),7.94(1H,s), 8.10(1H,s), 8.26(1H,s), 11.40(1H,brs).

mp: 294 to 296° C.

IR(ATR)cm⁻¹: 1594, 1562, 1494, 1382, 1332, 1159, 1118, 993, 817, 755,723.

MS m/z: 572(M⁺).

EI-MS: 571.9962 (Calcd for C₂₂H₁₆O₄N₄Cl₂F₂S₂: 571.9958).

Elemental Analysis for C₂₂H₁₆N₄O₄Cl₂F₂S₂: Calculated: C, 46.08; H, 2.81;N, 9.77; Cl, 12.37; F, 6.63; S, 11.18. Found: C, 46.04; H, 2.77; N,9.74; Cl, 12.46; F, 6.90; S, 11.21.

Example 269N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]-1-pyridin-4-ylmethanesulfonamide

To a methylene chloride (2 ml) solution of the[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine(104 mg, 0.242 mmol) obtained in Example 196 and pyridine (74 μl, 0.533mmol) was added (4-pyridylmethyl)sulfonyl chloride triflate (91 mg,0.266 mmol). The resulting mixture was stirred at room temperature for17 hours. To the reaction mixture were added pyridine (74 μl, 0.533mmol) and (4-pyridylmethyl)sulfonyl chloride triflate (91 mg, 0.266mmol). The resulting mixture was stirred at room temperature for 19hours. The reaction mixture was diluted with ethyl acetate. The dilutedsolution was washed with water and brine, dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure. The residue thus obtained was subjected to silica gel columnchromatography. The fraction obtained from the methanol:methylenechloride (=1:40) eluate was concentrated under reduced pressure to givethe title compound (66 mg, 0.113 mmol, 47%) as a white solid.

¹H-NMR(400 MHz,DMSO-d₆)δ: 4.88(2H,s), 6.30(1H,s), 7.27(2H,d,J=6.0 Hz),7.29-7.49(3H,m), 7.70(2H,d,J=8.8 Hz), 7.74(1H,s), 7.79(2H,d,J=8.8 Hz),8.45(1H,s), 8.53(2H,d,J=6.0 Hz), 11.00(1H,brs).

mp: 257° C. (decomp.)

IR(ATR)cm⁻¹: 1592, 1490, 1467, 1340, 1326, 1280, 1238, 1186, 1155, 1128,1085, 1004, 966, 902, 869, 823.

MS m/z: 584(M⁺+H).

Elemental Analysis for C₂₄H₁₇N₃O₄Cl₂F₂S₂: Calculated: C, 49.32; H, 2.93;N, 7.19; Cl, 12.13; F, 6.50; S, 10.97. Found: C, 49.35; H, 3.12; N,7.17; Cl, 12.05; F, 6.43; S, 10.93.

Example 270N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]piperidine-1-sulfonamide

A pyridine (2 ml) solution of the[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine(101 mg, 0.235 mmol) obtained in Example 196 and piperidine-1-sulfonylchloride (48 mg, 0.259 mmol) was stirred at 70° C. for 19 hours. To thereaction mixture was added piperidine-1-sulfonyl chloride (48 mg, 0.259mmol) and the resulting mixture was stirred at 70° C. for 4 days. Thereaction mixture was returned to room temperature and then, concentratedunder reduced pressure. The residue thus obtained was diluted with ethylacetate. The diluted solution was washed with water and brine, driedover anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate (=4:1) eluate was concentratedunder reduced pressure to yield a white solid. The resulting solid waswashed with hexane-ether, and collected by filtration to give the titlecompound (63 mg, 0.109 mmol, 47%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 1.51-1.61(2H,m), 1.65-1.75(4H,m),3.38(4H,t,J=4.6 Hz), 6.21(1H,s), 6.94-7.10(2H,m), 7.41-7.52(3H,m),7.70(2H,d,J=8.6 Hz), 8.24(1H,s), 8.29(1H,s), 8.71(1H,brs)

mp: 192 to 194° C.

IR(ATR)cm⁻¹: 1598, 1563, 1492, 1396, 1346, 1322, 1234, 1145, 1083, 998,923, 900, 833.

MS m/z: 576(M⁺+H).

Elemental Analysis for C₂₃H₂₁N₃O₄Cl₂F₂S₂: Calculated: C, 47.92; H, 3.67;N, 7.29; Cl, 12.30; F, 6.59; S, 11.12. Found: C, 47.87; H, 3.66; N,7.33; Cl, 12.12; F, 6.66; S, 11.25.

Example 271N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]-4-methylpiperidine-1-sulfonamide

An acetonitrile (5 ml) solution of the[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine(101 mg, 0.235 mmol) obtained in Example 196,4-methylpiperazine-1-sulfonyl chloride hydrochloride (126 mg, 0.534mmol) and triethylamine (150 μl, 1.07 mmol) was heated under reflux for23 hours. To the reaction mixture were added4-methylpiperazine-1-sulfonyl chloride hydrochloride (126 mg, 0.534mmol) and triethylamine (150 μl, 1.07 mmol). The resulting mixture washeated under reflux for 22 hours. The reaction mixture was returned toroom temperature and then, concentrated under reduced pressure. To theresidue thus obtained was added water and the resulting mixture wasextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel column chromatography. The fractionobtained from the methanol:methylene chloride (=1:20) eluate wasconcentrated under reduced pressure to give the title compound (34 mg,0.057 mmol, 16%) as a pale yellow solid.

¹H-NMR(400 MHz,CDCl₃)δ: 2.31(3H,s), 2.45-2.60(4H,m), 3.38-3.52(4H,m),6.20(1H,s), 6.95-7.10(2H,m), 7.41-7.50(3H,m), 7.69(2H,d,J=8.8 Hz),8.24(1H,s), 8.26(1H,s).

mp: 215 to 218° C.

IR(ATR)cm⁻¹: 1600, 1565, 1496, 1392, 1348, 1330, 1157, 1093, 935, 835,819.

MS m/z: 591(M⁺+H).

Elemental Analysis for C₂₃H₂₂N₄O₄Cl₂F₂S₂: Calculated: C, 46.70; H, 3.75;N, 9.47; Cl, 11.99; F, 6.42; S, 10.84. Found: C, 46.89; H, 3.76; N,9.40; Cl, 11.78; F, 6.42; S, 10.72.

Example 2723-Chloro-N-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]-N-(3-chloropropylsulfonyl)propane-1-sulfonamide

To a methylene chloride (5 ml) solution of the[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine(130 mg, 0.303 mmol) obtained in Example 196 and triethylamine (42 μl,0.303 mmol) was added 3-chloropropanesulfonyl chloride (37 μl, 0.303mmol) at 0° C. The reaction mixture was stirred at room temperature for2.5 hours. At 0° C., triethylamine (42 μl, 0.303 mmol) and3-chloropropanesulfonyl chloride (37 μl, 0.303 mmol) were addedsequentially. The resulting mixture was stirred at room temperature for7 hours. To the reaction mixture was added ethyl acetate. The resultingmixture was washed with a saturated aqueous solution of sodiumbicarbonate, dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure. The residue thusobtained was subjected to silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate (=5:1) eluate was concentratedunder reduced pressure. To the residue thus obtained was added ether andthe solid thus precipitated was collected by filtration to give thetitle compound as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 2.47-2.57(4H,m), 3.74(4H,t,J=6.1 Hz),3.96-4.05(4H,m), 6.20(1H,s), 6.98-7.15(2H,m), 7.40-7.53(3H,m),7.62(2H,d,J=8.3 Hz), 8.22(1H,s), 8.64(1H,s).

MS m/z: 709,711(M⁺+H).

Example 2733-Chloro-N-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]propane-1-sulfonamide

To a tetrahydrofuran (5 ml) solution of3-chloro-N-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]-N-(3-chloropropylsulfonyl)propane-1-sulfonamide(193 mg, 0.272 mmol) was added to a tetrahydrofuran solution (11.0M,0.28 ml, 0.28 mmol) of tetrabutylammonium fluoride. The resultingmixture was stirred at room temperature for 1 hour. To the reactionmixture was added a saturated aqueous solution of ammonium chloride,followed by extraction with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure. The residue thusobtained was subjected to silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate (=4:1) eluate was concentratedunder reduced pressure to give the title compound (108 mg, 0.190 mmol,70%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 2.35-2.44(2H,m), 3.61-3.67(2H,m),3.70(2H,t,J=6.1 Hz), 6.19(1H,s), 6.90-6.99(1H,m), 7.02-7.10(1H,m),7.42-7.53(3H,m), 7.64(2H,d,J=8.3 Hz), 7.84(1H,brs), 8.01(1H,s),8.31(1H,s).

IR(ATR)cm⁻¹: 1596, 1560, 1488, 1384, 1336, 1234, 1145, 1083, 997, 925,844.

MS m/z: 568,570(M⁺).

Example 2745-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-2-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)pyridine

An acetonitrile (5 ml) solution of3-chloro-N-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]propane-1-sulfonamide(83 mg, 0.146 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (26 μl, 0.175mmol) was stirred at 70° C. for 4.5 hours. The reaction mixture wasreturned to room temperature and then, concentrated under reducedpressure. The residue thus obtained was diluted with ethyl acetate. Thediluted solution was washed sequentially with 1N hydrochloric acid, asaturated aqueous solution of sodium bicarbonate and brine, dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate (=1:1) eluate was concentrated under reducedpressure to give the title compound (75 mg, 0.141 mmol, 96%) as a whitesolid.

¹H-NMR(400 MHz,CDCl₃)δ: 2.52-2.62(2H,m), 3.47(2H,t,J=7.6 Hz),4.02(2H,t,J=6.6 Hz), 6.24(1H,s), 6.95-7.10(2H,m), 7.44(2H,d,J=8.6 Hz),7.49-7.56(1H,m), 7.74(2H,d,J=8.6 Hz), 8.13(1H,s), 8.24(1H,s).

mp: 219 to 221° C.

IR(ATR)cm⁻¹: 1587, 1496, 1467, 1386, 1346, 1315, 1278, 1238, 1137, 1089,998, 831.

MS m/z: 532(M⁺).

Elemental Analysis for C₂₁H₁₆N₂O₄Cl₂F₂S₂: Calculated: C, 47.29; H, 3.02;N, 5.25; Cl, 13.29; F, 7.12; S, 12.02. Found: C, 47.39; H, 3.02; N,5.37; Cl, 13.32; F, 7.24; S, 11.95.

Example 275N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]-N-(trifluoromethylsulfonyl)trifluoromethanesulfonamide

To a methylene chloride (5 ml) solution of the[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine(103 mg, 0.240 mmol) obtained in Example 196 and pyridine (19 μl, 0.240mmol) was added trifluoromethanesulfonic anhydride (39 μl, 0.240 mmol)at 0° C. After the resulting mixture was stirred at room temperature for3 hours, pyridine (19 μl, 0.240 mmol) and trifluoromethanesulfonicanhydride (39 μl, 0.240 mmol) were added at 0° C. The resulting mixturewas stirred at room temperature for 15 hours, followed by concentrationunder reduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate (=5:1) eluate was concentrated under reducedpressure to give the title compound (84 mg, 0.120 mmol, 50%) as a whitesolid.

¹H-NMR(400 MHz,CDCl₃)δ: 6.23(1H,s), 6.99-7.15(2H,m), 7.38-7.48(3H,m),7.62(2H,d,J=8.8 Hz), 8.36(1H,s), 8.53(1H,s).

IR(ATR)cm⁻¹: 1581, 1498, 1442, 1332, 1214, 1159, 1122, 1085, 997, 944,923, 865, 755.

MS m/z: 693(M⁺+H).

Example 276N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]trifluoromethanesulfonamide

To a solution ofN-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]-N-(trifluoromethylsulfonyl)trifluoromethanesulfonamide(77 mg, 0.111 mmol) in a mixture of tetrahydrofuran (5 ml) and water (1ml) was added lithium hydroxide monohydrate (5.0 mg, 0.111 mmol). Theresulting mixture was stirred at room temperature for 5 hours. To thereaction mixture was added a saturated aqueous solution of ammoniumchloride, followed by extraction with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure. Theresidue thus obtained was subjected to silica gel column chromatography.The fraction obtained from the hexane:ethyl acetate (=2:1) eluatecontaining 0.5% trifluoroacetic acid was concentrated under reducedpressure. To the residue thus obtained was added ether, and the solidthus precipitated was collected by filtration to give the title compound(39 mg, 0.069 mmol, 63%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 6.21(1H,s), 6.95-7.03(1H,m), 7.06-7.15(1H,m),7.42-7.52(3H,m), 7.71(2H,d,J=8.8 Hz), 8.23(1H,s), 8.71(1H,s).

mp: 221 to 223° C.

IR(ATR)cm⁻¹: 1637, 1496, 1382, 1336, 1195, 1157, 1130, 1085, 1010, 923,779, 754.

MS m/z: 560(M⁺).

Elemental Analysis for C₁₉H₁₁N₂O₄Cl₂F₅S₂: Calculated: C, 40.65; H, 1.98;N, 4.99; Cl, 12.63; F, 16.92; S, 11.42. Found: C, 40.68; H, 1.94; N,5.06; Cl, 12.46; F, 16.91; S, 11.47.

Example 277N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]ethylenesulfonamide

To a methylene chloride (10 ml) solution of the[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine(982 mg, 2.29 mmol) obtained in Example 196 and 2-chloroethanesulfonylchloride (0.29 ml, 2.74 mmol) was added pyridine (0.44 ml, 5.49 mmol).The resulting mixture was stirred at room temperature for 3.5 hours. Tothe reaction mixture were added 2-chloroethanesulfonyl chloride (143 μl,1.37 mmol) and pyridine (222 μl, 2.75 mmol). The resulting mixture wasstirred at room temperature for 1 hour. Ethyl acetate was added to thereaction mixture. The resulting mixture was washed with a saturatedaqueous solution of sodium bicarbonate, dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated under reducedpressure. The residue thus obtained was subjected to flash silica gelcolumn chromatography. The fraction obtained from the hexane:ethylacetate (=3:1) eluate was concentrated under reduced pressure to givethe title compound (573 mg, 1.10 mmol, 48%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 6.17-6.25(2H,m), 6.65-6.70(2H,m),6.91-7.10(2H,m), 7.41-7.49(3H,m), 7.66(2H,d,J=8.6 Hz), 8.16(1H,s),8.33(1H,s)

IR(ATR)cm⁻¹: 1600, 1565, 1492, 1388, 1349, 1322, 1147, 1081, 998, 916,821, 757.

MS m/z: 519(M⁺+H).

Example 278N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]-2-piperidin-1-ylethanesulfonamide

To an ethanol (5 ml) solution ofN-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]ethylenesulfonamide(34 mg, 0.065 mmol) was added piperidine (10 μl, 0.098 mmol). Theresulting mixture was stirred at room temperature for 3 days. Thereaction mixture was concentrated under reduced pressure. The residuethus obtained was subjected to flash silica gel column chromatography.The fraction obtained from the methanol:methylene chloride (=1:30)eluate was concentrated under reduced pressure to give the titlecompound (35 mg, 0.058 mmol, 89%) as an amorphous substance. Theresulting amorphous substance was solidified by adding ethanol theretoand collected by filtration to give the title compound as a whitepowder.

¹H-NMR(400 MHz,CDCl₃)δ: 1.45-1.76(6H,m), 2.50-2.65(4H,m),2.97(2H,t,J=5.9 Hz), 3.30-3.38(2H,m), 6.21(1H,s), 6.92-7.10(2H,m),7.44(2H,d,J=8.6 Hz), 7.52-7.59(1H,m), 7.69(2H,d,J=8.6 Hz), 8.06(1H,s),8.22(1H,s).

mp: 200 to 203° C.

IR(ATR)cm⁻¹: 1600, 1571, 1492, 1390, 1332, 1141, 1083, 1002, 962, 919,811, 754.

MS m/z: 604(M⁺+H).

Elemental Analysis for C₂₅H₂₅N₃O₄Cl₂F₂S₂: Calculated: C, 49.67; H, 4.17;N, 6.95; Cl, 11.73; F, 6.29; S, 10.61. Found: C, 49.90; H, 4.13; N,6.88; Cl, 11.64; F, 6.17; S, 10.52.

Example 279N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]-2-(dimethylamino)ethanesulfonamide

To a tetrahydrofuran (3 ml) solution of theN-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]ethylenesulfonamide(64 mg, 0.123 mmol) obtained in Example 277 was added a dimethylaminetetrahydrofuran solution (2M, 0.18 ml, 0.36 mmol). The resulting mixturewas stirred at room temperature for 3 days, followed by concentrationunder reduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from themethanol:methylene chloride (=1:20) eluate was concentrated underreduced pressure to give the title compound (67 mg, 0.117 mmol, 97%) asa white solid. The resulting solid was washed with ethanol and collectedby filtration to give the title compound (43 mg) as a white powder.

¹H-NMR(400 MHz,CD₃OD)δ: 2.73(6H,s), 3.37(2H,t,J=7.0 Hz), 3.82(2H,t,J=7.0Hz), 6.31(1H,s), 7.16-7.26(2H,m), 7.53-7.65(3H,m), 7.75(2H,d,J=8.8 Hz),7.84(1H,s), 8.24(1H,s).

IR(ATR)cm⁻¹: 1587, 1494, 1455, 1321, 1151, 1087, 998, 757.

MS m/z: 564(M⁺+H).

FAB-MS: 564.0399 (Calcd for C₂₂H₂₂O₄N₃Cl₂F₂S₂: 564.0397).

Example 280N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]-2-morpholin-4-ylethanesulfonamide

To an ethanol (3 ml) solution of theN-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]ethylenesulfonamide(53 mg, 0.102 mmol) obtained in Example 277 was added morpholine (18 μl,0.204 mmol). The resulting mixture was stirred at room temperature for 3days, followed by concentration under reduced pressure. The residue thusobtained was subjected to flash silica gel column chromatography. Thefraction obtained from the methanol:methylene chloride (=1:40) eluatewas concentrated under reduced pressure. Ether was added to the residuethus obtained. The solid thus precipitated was collected by filtrationto give the title compound (45 mg, 0.074 mmol, 73%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 2.51-2.60(4H,m), 2.96(2H,t,J=6.1 Hz),3.36-3.45(2H,m), 3.70-3.80(4H,m), 6.22(1H,s), 6.90-7.10(2H,m),7.45(2H,d,J=8.8 Hz), 7.50-7.59(1H,m), 7.68(2H,d,J=8.8 Hz), 8.19(1H,s),8.24(1H,s).

mp: 219 to 221° C.

IR(ATR)cm⁻¹: 1602, 1565, 1492, 1388, 1321, 1286, 1238, 1147, 1116, 1083,998.

MS m/z: 606(M⁺+H)

FAB-MS: 606.0499 (Calcd for C₂₄H₂₄O₅N₃Cl₂F₂S₂: 606.0503).

Elemental Analysis for C₂₄H₂₃N₃O₅Cl₂F₂S₂: Calculated: C, 47.53; H, 3.82;N, 6.93; Cl, 11.69; F, 6.27; S, 10.57. Found: C, 47.73; H, 3.84; N,6.97; Cl, 11.72; F, 6.25; S, 10.72.

Example 281 t-Butyl4-[2-[[[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]sulfonyl]ethyl]piperazine-1-carboxylate

To an ethanol (3 ml) solution of theN-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]ethylenesulfonamide(59 mg, 0.114 mmol) obtained in Example 277 was added1-(t-butoxycarbonyl)piperazine (32 mg, 0.170 mmol). The resultingmixture was stirred at room temperature for 3 days, followed byconcentration under reduced pressure. The residue thus obtained wassubjected to flash silica gel column chromatography. The fractionobtained from the methanol:methylene chloride (=1:40) eluate wasconcentrated under reduced pressure to give the title compound (75 mg,0.106 mmol, 93%) as an amorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 1.46(9H,s), 2.50(4H,t,J=5.0 Hz), 2.97(2H,t,J=6.0Hz), 3.35-3.42(2H,m), 3.44-3.54(4H,m), 6.22(1H,s), 6.90-7.10(2H,m),7.45(2H,d,J=8.8 Hz), 7.50-7.58(1H,m), 7.68(2H,d,J=8.8 Hz), 8.19(1H,s),8.24(1H,s).

IR(ATR)cm⁻¹ : 1691, 1592, 1494, 1330, 1240, 1147, 1083, 998, 755.

MS m/z: 705(M⁺+H).

Example 282N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]-2-piperazin-1-ylethanesulfonamide

To an ethanol (5 ml) solution of t-butyl4-[2-[[[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]sulfonyl]ethyl]piperazine-1-carboxylate(72 mg, 0.102 mmol) was added concentrated hydrochloric acid (1 ml). Theresulting mixture was stirred at room temperature for 2 days, followedby concentration under reduced pressure. To the residue thus obtainedwas added a saturated aqueous solution of sodium bicarbonate. Theresulting mixture was extracted with methylene chloride. The organiclayer was dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure. The residue thusobtained was washed with ether to give the title compound (23 mg, 0.038mmol, 37%) as a white powder.

¹H-NMR(400 MHz,DMSO-d₆)δ: 2.40-2.47(4H,m), 2.62-2.70(2H,m),2.83-2.90(4H,m), 6.15(1H,s), 7.25-7.42(3H,m), 7.47-7.55(1H,m),7.68(2H,d,J=8.7 Hz), 7.77(2H,d,J=8.7 Hz), 8.03(1H,s).

MS m/z: 605(M⁺+H).

Example 283 Ethyl[[[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]sulfonyl]acetate

To a methylene chloride (10 ml) solution of the[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine(331 mg, 0.771 mmol) obtained in Example 196 and pyridine (94 μl, 1.16mmol) was added a methylene chloride (2 ml) solution of ethylchlorosulfonylacetate (216 mg, 1.16 mmol) at 0° C. After the resultingmixture was stirred at room temperature for 12 hours, pyridine (94 up,1.16 mmol) and a methylene chloride (2 ml) solution of ethylchlorosulfonylacetate (216 mg, 1.16 mmol) were added sequentially at 0°C. The resulting mixture was stirred at room temperature for 9 hours andthen, the reaction mixture was concentrated under reduced pressure. Tothe residue thus obtained was added ethyl acetate. The resulting mixturewas washed sequentially with a saturated aqueous solution of sodiumbicarbonate and brine, dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure. Theresidue thus obtained was subjected to flash silica gel columnchromatography. The fraction obtained from the hexane:ethyl acetate(=3:1) eluate was concentrated under reduced pressure to give the titlecompound (239 mg, 0.412 mmol, 53%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 1.29(3H,t,J=7.2 Hz), 4.25(2H,q,J=7.2 Hz),4.37(2H,s), 6.21(1H,s), 6.91-7.10(2H,m), 7.45(2H,d,J=8.6 Hz),7.50-7.58(1H,m), 7.66(2H,d,J=8.6 Hz), 8.09(1H,s), 8.30(1H,s).

IR(ATR)cm⁻¹: 1745, 1600, 1567, 1496, 1386, 1355, 1317, 1280, 1232, 1147,1081.

MS m/z: 579(M⁺+H).

Example 284N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]-2-hydroxyethanesulfonamide

To a tetrahydrofuran (5 ml) solution of ethyl[[[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]sulfonyl]acetate(67 mg, 0.116 mmol) was added an ether solution (0.18 ml) of 1M lithiumaluminum hydride at 0° C. The resulting mixture was stirred at 0° C.After the termination of the reaction was confirmed by TLC, a saturatedaqueous solution of ammonium chloride was added to the reaction mixture.The resulting mixture was filtered through Celite. The filtrate wasdried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate (=2:1) eluate was concentratedunder reduced pressure to give the title compound (39 mg, 0.073 mmol,63%) as a white solid.

¹H-NMR(400 MHz,DMSO-d₆)δ: 3.63 (2H,t,J=6.3 Hz), 3.75-3.85(2H,m),4.94(1H,brs), 6.28(1H,s), 7.28-7.55(3H,m), 7.70(2H,d,J=8.7 Hz),7.80(2H,d,J=8.7 Hz), 7.81(1H,s), 8.37(1H,s), 10.91(1H,brs).

mp: 155 to 158° C.

IR(ATR)cm⁻¹: 3093, 2867, 1600, 1565, 1492, 1392, 1322, 1139, 1083, 813,754.

MS m/z: 536(M⁺).

EI-MS: 535.9835 (Calcd for C₂₀H₁₆O₅N₂Cl₂F₂S₂: 535.9846).

Elemental Analysis for C₂₀H₁₆N₂O₅Cl₂F₂S₂.0.5H₂O: Calculated: C, 43.96;H, 3.14; N, 5.13; Cl, 12.98; F, 6.95; S,11.74. Found: C, 44.22; H, 3.07;N, 5.13; Cl, 12.89; F, 7.10; S, 11.65.

Example 2852-[[[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]sulfonyl]acetamide

To a methanol solution (5 ml) of 7N ammonia was added the ethyl[[[5-chloro-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]sulfonyl]acetate(78 mg, 0.135 mmol) obtained in Example 283. The resulting mixture wasstirred at room temperature for 3 days, followed by concentration underreduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from themethanol:methylene chloride (=1:25) eluate was concentrated underreduced pressure to give the title compound (66 mg, 0.120 mmol, 89%) asa white solid.

¹H-NMR (400 MHz,DMSO-d₆)δ: 4.33(2H,s), 6.29(1H,s), 7.29-7.56(4H,m),7.64-7.72(3H,m), 7.76-7.84(3H,m), 8.35(1H,s), 11.16(1H,brs).

IR(ATR)cm⁻¹: 1691, 1596, 1565, 1492, 1382, 1322, 1238, 1149, 1083, 995,966, 811.

MS m/z: 550(M⁺+H).

Elemental Analysis for C₂₀H₁₅N₃O₅Cl₂F₂S₂.0.5H₂O: Calculated: C, 42.94;H, 2.88; N, 7.51; Cl, 12.68; F, 6.79; S, 11.46. Found: C, 42.64; H,2.73; N, 7.46; Cl, 12.57; F, 6.97; S, 11.48.

Example 286[[[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]sulfonyl]aceticacid

To a solution of the ethyl[[[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]sulfonyl]acetate(60 mg, 0.104 mmol) obtained in Example 283 in a mixture oftetrahydrofuran (5 ml) and water (1 ml) was added lithium hydroxidemonohydrate (9.1 mg, 0.218 mmol). The resulting mixture was stirred atroom temperature for 2 hours. To the reaction mixture was added 1Nhydrochloric acid. The resulting mixture was extracted with methylenechloride. The extract was dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure. Theresidue thus obtained was subjected to silica gel column chromatography.The fraction obtained from the methanol:methylene chloride (=1:30)eluate containing 0.5% trifluoroacetic acid was concentrated underreduced pressure to give the title compound (54 mg, 0.098 mmol, 94%) asa white solid.

¹H-NMR(400 MHz,DMSO-d₆)δ: 4.45-4.60(2H,m), 6.29(1H,s), 7.29-7.55(3H,m),7.69(2H,d,J=8.9 Hz), 7.80(2H,d,J=8.9 Hz), 7.81(1H,s), 8.38(1H,s).

MS m/z: 551(M⁺+H).

Example 287(Z)-5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-2-(3-[1,3]dioxolan-2-ylpropenyl)pyridine(Isomer 287-A) and(E)-5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-2-(3-[1,3]dioxolan-2-ylpropenyl)pyridine(Isomer 287-B)

Under an argon atmosphere, n-butyl lithium (a 1.59M hexane solution, 1.3ml, 1.99 mmol) was added to a tetrahydrofuran (30 ml) solution of2-(1,3-dioxolan-2-yl)ethyltriphenylphosphonium bromide (738 mg, 1.99mmol) at −78° C. The resulting mixture was stirred for 1 hour. To thereaction mixture was added the[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbaldehyde(400 mg, 0.904 mmol) obtained in Example 258. The temperature of theresulting mixture was raised to room temperature, followed by stirringfor 4 hours. To the reaction mixture was added a saturated aqueoussolution of ammonium chloride. The resulting mixture was then extractedwith dichloromethane. The organic layer was dried over magnesiumsulfate, and concentrated under reduced pressure. The residue thusobtained was subjected to flash silica gel column chromatography. Thefraction obtained from the hexane:ethyl acetate=4:1 eluate wasconcentrated under reduced pressure to give Isomer 287-A (low polar)(140 mg, 0.266 mmol, 29%) as a colorless amorphous substance and Isomer287-B (high polar) (170 mg, 0.323 mmol, 36%) as a colorless amorphoussubstance.

Isomer 287-A

¹H-NMR(400 MHz,CDCl₃)δ: 3.03-3.17(2H,m), 3.88-4.10(4H,m),5.11(1H,t,J=4.3 Hz), 6.10(1H,dt,J=12.0,7.6 Hz), 6.25(1H,s),6.65(1H,d,J=12.0 Hz), 6.93-6.99(1H,m), 7.03-7.09(1H,m), 7.44(2H,d,J=8.6Hz), 7.61(2H,d,J=8.6 Hz), 7.67-7.71(1H,m), 8.10(1H,s), 8.49(1H,s).

MS m/z: 526(M⁺+H).

Isomer 287-B

¹H-NMR(400 MHz,CDCl₃)δ: 2.67-2.71(2H,m), 3.88-4.08(4H,m),5.07(1H,t,J=4.6 Hz), 6.20(1H,s), 6.68(1H,d,J=15.9 Hz), 6.85-7.00(2H,m),7.02-7.08(1H,m), 7.44(2H,d,J=8.1 Hz), 7.55-7.62(1H,m), 7.61(2H,d,J=8.1Hz), 7.96(1H,s), 8.43(1H,s).

MS m/z: 526(M⁺+H).

Example 2884-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]butylaldehyde

After a water suspension of Raney nickel (“R-100”, product of Nikko RicaCorporation) was washed sequentially with water and ethanol, ethanol wasadded thereto to give a corresponding ethanol suspension. The resultingethanol suspension (1 ml) was added to a solution of (Z) and(E)-5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-2-(3-[1,3]dioxolan-2-ylpropenyl)pyridine(80 mg, 0.152 mmol) in a mixture of ethanol (5 ml) and 1,4-dioxane (3ml). Under a hydrogen atmosphere of 1 atmospheric pressure, theresulting mixture was stirred vigorously for 30 minutes. After thereaction mixture was filtered, the filtrate was concentrated underreduced pressure.

To a 1,4 dioxane (4 ml) solution of the residue thus obtained was addedconcentrated hydrochloric acid (1 ml) and the resulting mixture wasstirred at room temperature for 1 hour. The solvent was thenconcentrated under reduced pressure. To the residue thus obtained wasadded a saturated aqueous solution of sodium bicarbonate, followed byextraction with ethyl acetate. The organic layer was washed with brine.The organic layer thus obtained was dried over magnesium sulfate, andconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate=4:1 eluate was concentrated underreduced pressure to give the title compound (44 mg, 0.0908 mmol, 59%) asa colorless amorphous substance.

¹H-NMR(400 MHz,CDCl₃)δ: 2.09-2.17(2H,m), 2.56(2H,td,J=7.3,1.5 Hz),2.92(2H,t,J=7.7 Hz), 6.21(1H,s), 6.92-6.97(1H,m), 7.03-7.08(1H,m),7.45(2H,d,J=8.6 Hz), 7.51-7.55(1H,m), 7.61(2H,d,J=8.6 Hz), 7.95(1H,s),8.47(1H,s), 9.81(1H,t,J=1.5 Hz)

MS m/z: 484(M⁺+H).

Example 2894-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]butyricacid

To a formic acid (1 ml) solution of4-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]butylaldehyde(40 mg, 0.0828 mmol) was added 30% aqueous hydrogen peroxide (84 μl,0.745 mmol). The resulting mixture was stirred at room temperature for 9hours. Water was added to the reaction mixture, followed by extractionwith ethyl acetate. The organic layer was washed sequentially with waterand brine. The organic layer was dried over magnesium sulfate, andconcentrated under reduced pressure. The residue thus obtained wasrecrystallized from hexane:ethyl acetate to give the title compound (13mg, 0.0260 mmol, 32%) as a white powder.

¹H-NMR(400 MHz,CDCl₃)δ: 2.16-2.18(2H,m), 2.46(2H,t,J=7.2 Hz),2.99(2H,t,J=7.5 Hz), 6.22(1H,s), 6.92-6.98(1H,m), 7.03-7.08(1H,m),7.45(2H,d,J=8.6 Hz), 7.51-7.56(1H,m), 7.61(2H,d,J=8.6 Hz), 8.00(1H,s),8.49(1H,s).

mp: 147 to 148° C.

MS m/z: 500(M⁺+H).

Example 2902-Bromomethyl-5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine

To a dichloromethane (15 ml) solution of the[5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]methanol(582 mg, 1.41 mmol) obtained in Example 256 were sequentially addedcarbon tetrabromide (936 mg, 2.82 mmol) and triphenylphosphine (407 mg,1.55 mmol) at 0° C. The resulting mixture was stirred at roomtemperature for 15 hours. The reaction mixture was concentrated underreduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=20:1 eluate was concentrated under reduced pressureto give the title compound (518 mg, 1.09 mmol, 77%) as a colorless oil.

¹H-NMR(400 MHz,CDCl₃)δ: 4.51(1H,d,J=10.5 Hz), 4.54(1H,d,J=10.5 Hz),6.03(1H,s), 6.94-7.06(2H,m), 7.10-7.16(1H,m), 7.23(2H,d,J=8.5 Hz),7.28(2H,d,J=8.5 Hz), 7.73(1H,s), 8.49(1H,s).

MS m/z: 474,476(M⁺+H).

Example 291[5-Chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]acetonitrile

Under an argon atmosphere, trimethylsilylnitrile (0.226 ml, 1.63 mmol)and a tetrahydrofuran solution (1M, 1.63 ml, 1.63 mmol) oftetrabutylammonium fluoride were added sequentially to an acetonitrile(10 ml) solution of2-bromomethyl-5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine(516 mg, 1.09 mmol) at room temperature. The resulting mixture wasstirred for 30 minutes. The reaction mixture was concentrated underreduced pressure. The residue thus obtained was subjected to flashsilica gel column chromatography. The fraction obtained from thehexane:ethyl acetate=9:1 eluate was concentrated under reduced pressureto give the title compound (390 mg, 0.93 mmol, 85%) as a brown oil.

¹H-NMR(400 MHz,CDCl₃)δ: 3.90(1H,d,J=19.0 Hz), 3.95(1H,d,J=19.0 Hz),6.04(1H,s), 6.96-7.07(2H,m), 7.12-7.18(1H,m), 7.24(2H,d,J=8.8 Hz),7.29(2H,d,J=8.8 Hz), 7.67(1H,s), 8.52(1H,s).

MS m/z: 421(M⁺+H).

Example 292[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]acetonitrile

To an ethyl acetate (5 ml) solution of[5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]acetonitrile(387 mg, 0.92 mmol) were added methanol (5 ml), 31% aqueous hydrogenperoxide (3 ml) and hexaammonium heptamolybdate tetrahydrate (227 mg,0.18 mmol). The resulting mixture was stirred at room temperature for 2hours. Water was added to the reaction mixture. Ethyl acetate andmethanol were distilled off under reduced pressure. To the residue wasadded a saturated aqueous solution of sodium bicarbonate. The productthus obtained was extracted with dichloromethane. The organic layer wasdried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure. The residue thus obtained wassubjected to flash silica gel column chromatography. The fractionobtained from the hexane:ethyl acetate=17:3 eluate was concentratedunder reduced pressure to give the title compound (364 mg, 0.80 mmol,87%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 4.02(2H,s), 6.22(1H,s), 6.92-6.99(1H,m),7.04-7.11(1H,m), 7.46(2H,d,J=8.6 Hz), 7.48-7.54(1H,m), 7.62(2H,d,J=8.6Hz), 8.15(1H,s), 8.56(1H,s).

MS m/z: 453(M⁺+H).

Example 293[5-Chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]aceticacid

To an acetic acid (2 ml) solution of[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]acetonitrile(113 mg, 0.25 mmol) was added a mixture of water (2 ml) and concentratedsulfuric acid (2 ml) at room temperature. The resulting mixture wasstirred at 100° C. for 2 hours. After the reaction mixture was cooled toroom temperature, water was added thereto. The resulting mixture wasextracted with dichloromethane. The organic layer was dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure. The residue thus obtained was washed with amixed solvent of diethyl ether/hexane and then, collected by filtrationto give the title compound (101 mg, 0.21 mmol, 86%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 1.74(1H,brs), 4.00(1H,d,J=17.9 Hz),4.05(1H,d,J=17.9 Hz), 6.23(1H,s), 6.92-6.99(1H,m), 7.04-7.11(1H,m),7.45(2H,d,J=8.6 Hz), 7.48-7.54(1H,m), 7.62(2H,d,J=8.6 Hz), 8.12(1H,s),8.52(1H,s).

MS m/z: 472(M⁺+H).

Referential Example 53(2,5-Dichloro-4-pyridyl)(2,6-difluorophenyl)methanol

Under an argon atmosphere, n-butyl lithium (a 1.60M hexane solution,2.33 ml, 3.72 mmol) was added to a tetrahydrofuran solution (12 ml) ofdiisopropylamine (0.520 ml, 3.72 mmol) at −78° C. The resulting mixturewas then stirred at −78° C. for 30 minutes. To the reaction mixture wasadded a tetrahydrofuran solution (2 ml) of 2,5-dichloropyridine (500 mg,3.38 mmol). The resulting mixture was stirred at −78° C. for 1 hour. Atetrahydrofuran solution (2 ml) of 2,6-difluorobenzaldehyde (395 mg,3.72 mmol) was then added to the reaction mixture, followed by stirringat −78° C. for 2 hours. To the reaction mixture was added 1Nhydrochloric acid (7 ml) and then, the temperature of the reactionmixture was raised to room temperature. The reaction mixture was dilutedwith ethyl acetate. The diluted mixture was washed with water and brine,dried over magnesium sulfate, and concentrated. The solid thus obtainedwas washed with dichloromethane to give the title compound (746 mg, 2.57mmol, 76%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 2.62(1H,brd,J=3.7 Hz), 6.30(1H,brs),6.87-6.93(2H,m), 7.28-7.37(1H,m), 7.91(1H,s), 8.25(1H,s).

MSm/z: 290(M⁺+H).

Example 2942,5-Dichloro-4-[(4-chlorophenylsulfonyl)(2,6-difluorophenyl)methyl]pyridine

The (2,5-dichloro-4-pyridyl)(2,6-difluorophenyl)methanol (744 mg, 2.57mmol) obtained in Referential Example 53 was suspended indichloromethane (6 ml), followed by the addition of thionyl chloride(0.5 ml) and dimethylformamide (one drop). The resulting mixture wasstirred at room temperature for 5 hours. To the reaction mixture wasadded thionyl chloride (1.0 ml) further. The resulting mixture wasstirred at room temperature for 24 hours. The reaction mixture wasconcentrated. The residue thus obtained was neutralized with a saturatedsolution of sodium bicarbonate and then, extracted with dichloromethane.The extract was washed with water and brine, dried over magnesiumsulfate and concentrated. The residue thus obtained was dissolved indimethylformamide (10 ml). After the addition of sodium4-chlorobenzenesulfinate (613 mg, 3.08 mmol), the resulting mixture washeated at 50° C. for 5 hours and then, 80° C. for 3 hours. The reactionmixture was diluted with ethyl acetate. The diluted solution was washedwith water and brine, dried over magnesium sulfate, and concentrated.The residue thus obtained was subjected to flash silica gel columnchromatography. The fraction obtained from the hexane:ethyl acetate=4:1eluate was concentrated. The resulting solid was recrystallized fromdiethyl ether-hexane to give the title compound (761 mg, 1.69 mmol, 66%)as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 6.02(1H,s), 6.84-6.90(2H,m), 7.32-7.40(1H,m),7.46(2H,d,J=8.5 Hz), 7.65(2H,d,J=8.5 Hz), 8.35(1H,s), 8.43-8.46(1H,m).

MSm/z: 448(M⁺+H).

Example 2955-Chloro-4-[(4-chlorophenylsulfonyl)(2,6-difluorophenyl)methyl]-2-(3,4-dimethoxybenzylamino)pyridine

To an N-methyl-2-pyrrolidone solution (20 ml) of the2,5-dichloro-4-[(4-chlorophenylsulfonyl)(2,6-difluorophenyl)methyl]pyridine(755 mg, 1.68 mmol) obtained in Example 294 was added3,4-dimethoxybenzylamine (0.745 ml, 5.04 mmol) under an argonatmosphere. The resulting mixture was heated at 150° C. for 5 hours. Thereaction mixture was returned to room temperature and then, diluted withethyl acetate. The diluted solution was washed with a saturated aqueoussolution of ammonium chloride, a saturated aqueous solution of sodiumbicarbonate, water and brine, dried over magnesium sulfate, andconcentrated. The residue thus obtained was subjected to flash silicagel column chromatography. The fraction obtained from the hexane:ethylacetate=2:1 eluate was concentrated to give the title compound (295 mg,0.509 mmol, 30%) as a white amorphous substance.

¹H-NMR(400 MHz CDCl₃)δ: 3.89(3H,s), 3.90(3H,s), 4.48(2H,d,J=5.6 Hz),5.06(1H, t,J=5.6 Hz), 6.02(1H,s), 6.81-6.88(3H,m), 6.93-7.00(2H,m),7.28-7.36(1H,m), 7.40(2H,d,J=8.3 Hz), 7.51(1H,s), 7.56(2, d,J=8.3 Hz),8.00(1H,s).

MSm/z: 579(M⁺+H).

Example 2965-Chloro-4-[(4-chlorophenylsulfonyl)(2,6-difluorophenyl)methyl]pyridin-2-ylamine

The5-chloro-4-[(4-chlorophenylsulfonyl)(2,6-difluorophenyl)methyl]-2-(3,4-dimethoxybenzylamino)pyridine(293 mg, 0.506 mmol) obtained in Example 295 was dissolved intrifluoroacetic acid (4 ml). The resulting solution was heated at 65° C.for 2 hours. The reaction mixture was concentrated. The residue thusobtained was basified with a saturated aqueous solution of sodiumbicarbonate, followed by extraction with ethyl acetate. The extract waswashed with water and brine, dried over magnesium sulfate, andconcentrated. The residue thus obtained was subjected to flash silicagel column chromatography. The fraction obtained from the hexane:ethylacetate=2:1 eluate was concentrated. The solid thus obtained wasrecrystallized from ethyl acetate-hexane to give the title compound (147mg, 0.343 mmol, 68%) as a white solid.

¹H-NMR(400 MHz,CDCl₃)δ: 4.62(2H,s), 6.01(1H,s), 6.82-6.89(2H,m),7.29-7.38(1H,m), 7.44(2H,d,J=8.5 Hz), 7.59(1H,brs), 7.65(2H,d,J=8.5 Hz),7.99(1H,s).

IR(ATR)cm⁻¹: 3502, 3400, 1620, 1603, 1545, 1471, 1412, 1333, 1279, 1230,1151, 1084, 993, 928, 891, 829, 795, 756, 623, 559, 513, 459.

mp: 179 to 181° C.

MSm/z: 429(M⁺+H).

Elemental Analysis for C₁₈H₁₂Cl₂F₂N₂O₂S: Calculated: C, 50.36; H, 2.82;Cl, 16.52; F, 8.85; N, 6.53; S, 7.47. Found: C, 50.36; H, 2.83; Cl,16.39; F, 8.88; N, 6.48; S, 7.56.

Test Example

Measuring Method of an Inhibitor of the Production or Secretion ofβ-Amyloid Protein

The inhibitory activity against formation of β amyloid protein of thecompounds obtained in Examples was tested in the method describedbellow.

E35 cells were established by transfecting APP751 gene which is a wildtype human β-amyloid protein precursor into human glioma cells (H4cells).

E35 cells were seeded in 96-well plates and cultured in an incubator of37° C. by using a Dulbecco's Modified Eagle's Medium containing 10%inactivated fetal bovine serum (10% FBS-DMEM). Twenty-four hours afterseeding, a test compound dissolved in DMSO so as to give itsconcentration to be 2000 times as much as that of the finalconcentration was added to the medium in an amount of 1/2000 capacity ofthe culture medium. The cells were cultured for additional twenty-fourhours, and then the supernatant was collected. The amount of β amyloidprotein (Aβ) secreted in the supernatant was measured by the sandwichenzyme-linked immunosorbent assay (ELISA). Described specifically, amonoclonal antibody 25-1, which recognized Aβ25-35, was immobilized ontoa 96-well ELISA plate, followed by the incubation at 4° C. for 16 to 20hours. After washing with a phosphate buffer (pH 7.4) (PBS), abiotinylated monoclonal antibody MA32-40, which recognized Aβ1-8, wasadded, and the plate was kept at 4° C. for 2 hours. After thesupernatant was removed and the well was washed sufficiently with PBS,alkaline phosphatase-conjugated streptavidin was added to the plate.Absorbance was measured while adding BlouPhos (manufactured by KPL) as asubstrate. An amount of Aβ contained in the supernatant was calculatedusing a calibration curve separately created using Aβ of a knownconcentration. IC₅₀ of the test compound was presented as theconcentration at which 50% inhibition of Aβ production was observedcompared to the amount of Aβ of the control cells to which only DMSO wasadded.

On the other hand, cytotoxicity of the test compound was assayed in thefollowing manner. The test compound dissolved in DMSO was added to H4cells cultured on 10% FBS-DMEM. After incubation for 72 hours, a viablecell count was measured using Alamar Blue (manufactured by BIOSOURCE).Concentration of the test compounds at which the viable cell count was80% or less of the control cells to which only DMSO was added wasdefined as the concentration at which cytotoxicity appears.

When there is at least 10-times difference between the IC₅₀ and theconcentration at which cytotoxicity appears, then the compound is judgedas a compound having an inhibitory activity against production orsecretion of β amyloid protein.

The results of evaluation of the compound of the present invention usingthe above-described assay are shown in Table 1. Compounds exhibitingIC₅₀ not higher than 5 nM are evaluated as +++, those exhibiting IC₅₀ranging from 5 nM to 50 nM are evaluated as ++ and those exhibiting IC₅₀ranging from 50 to 500 nM are evaluated as +. TABLE 1 Compound Activity 1 +  19 +  20 +  23 (Compound A) ++  42 +  43 +  46 +  55 ++  56 ++  57++  59 ++  61 +++  82 +  84 + 106 +++ 109 ++ 111 ++ 114 ++ 115 +++ 116++ 164 +++ 168 +++ 176 +++ 196 +++ 197 +++ 203 ++ 211 +++ 215 +++ 216+++ 220 (B) + 221 +++ 222 ++ 225 ++ 234 +++ 236 +++ 239 + 240 ++ 241 ++242 + 243 ++ 245 ++ 246 ++ 247 +++ 249 +++ 250 ++ 251 +++ 254 + 261 ++267 ++ 268 +++ 269 +++ 270 ++ 271 +++ 274 ++ 276 ++ 278 +++ 279 +++ 280+++

1. A compound represented by the following formula (1):

(wherein, R¹ and R³ each independently represents an aromatichydrocarbon group which may have a substituent or an aromaticheterocyclic group which may have a substituent, R² represents asaturated or unsaturated monocyclic heterocyclic group or unsaturatedpolycyclic heterocyclic group which may have a substituent, R⁴represents a hydrogen atom or a C₁₋₆ alkyl group, X represents —S—, —SO—or —SO₂—); an N-oxide or S-oxide thereof; a salt thereof; or a solvatethereof.
 2. A compound according to claim 1, wherein R¹ and R³ eachindependently represents a phenyl group which may have a substituent; anN-oxide or S-oxide thereof; a salt thereof; or a solvate thereof.
 3. Acompound according to claim 1, wherein R¹ and R³ each independentlyrepresents an aromatic hydrocarbon group or aromatic heterocyclic groupwhich may have 1 to 3 substituents selected from halogen atoms, C₁₋₆alkyl groups, trihalogenomethyl groups, C₁₋₆ alkoxy groups, formylgroup, C₂₋₆ alkanoyl groups, carboxyl group, carboxyamino C₁₋₆ alkylgroups, C₁₋₆ alkoxycarbonylamino C₁₋₆ alkyl groups, oxo group, nitrogroup, cyano group, amidino group, C₂₋₆ alkenyloxy groups, hydroxygroup, thioxo group, amino group, C₁₋₆ alkylamino groups, di(C₁₋₆alkyl)amino groups, C₁₋₆ alkoxycarbonyl groups, carbamoyl group, C₁₋₆alkylcarbamoyl groups, di(C₁₋₆ alkyl)carbamoyl groups, thiocarbamoylgroup, C₁₋₆ alkylthiocarbamoyl groups, di(C₁₋₆ alkyl)thiocarbamoylgroups, mercapto group, C₁₋₆ alkylthio groups, C₁₋₆ alkylsulfinyl groupsand C₁₋₆ alkylsulfonyl groups; an N-oxide or S-oxide thereof; a saltthereof; or a solvate thereof.
 4. A compound according to claim 1,wherein R¹ and R³ each independently represents a phenyl group which mayhave 1 to 3 substituents selected from halogen atoms, C₁₋₆ alkyl groups,trihalogenomethyl groups, C₁₋₆ alkoxy groups, formyl group, C₂₋₆alkanoyl groups, carboxyl group, carboxyamino C₁₋₆ alkyl groups, C₁₋₆alkoxycarbonylamino C₁₋₆ alkyl groups, oxo group, nitro group, cyanogroup, amidino group, C₂₋₆ alkenyloxy groups, hydroxy group, thioxogroup, amino group, C₁₋₆ alkylamino groups, di(C₁₋₆ alkyl)amino groups,C₁₋₆ alkoxycarbonyl groups, carbamoyl group, C₁₋₆ alkylcarbamoyl groups,di(C₁₋₆ alkyl)carbamoyl groups, thiocarbamoyl group, C₁₋₆alkylthiocarbamoyl groups, di(C₁₋₆ alkyl)thiocarbamoyl groups, mercaptogroup, C₁₋₆ alkylthio groups, C₁₋₆ alkylsulfinyl groups and C₁₋₆alkylsulfonyl groups; an N-oxide or S-oxide thereof; a salt thereof; ora solvate thereof.
 5. A compound according to any one of claims 1 to 4,wherein R² represents a pyridyl group which may have a substituent; anN-oxide or S-oxide thereof; a salt thereof; or a solvate thereof.
 6. Acompound according to any one of claims 1 to 4, wherein R² represents amonocylic or polycyclic heterocyclic group which may have 1 to 3substituents selected from halogen atoms, cyano group, C₁₋₆ alkylgroups, hydroxy group, C₁₋₆ alkoxy groups, C₂₋₆ alkenyloxy groups,carboxy C₁₋₆ alkyl groups, C₁₋₆ alkoxycarbonyl C₁₋₆ alkyl groups,heterocyclic-carbonyl C₁₋₆ alkyl groups, hydroxy C₁₋₆ alkyl groups,C₆₋₁₀ aromatic hydrocarbon-sulfonyl C₁₋₆ alkyl groups,N,N-dialkylaminosulfonyl C₁₋₆ alkyl groups, heterocyclic-C₁₋₆ alkylgroups, C₆₋₁₀ aromatic hydrocarbon-C₁₋₆ alkyl groups, C₆₋₁₀ aromatichydrocarbon-thio C₁₋₆ alkyl groups, azido-C₁₋₆ alkyl groups, amino C₁₋₆alkyl groups, C₁₋₆ alkylamino C₁₋₆ alkyl groups, di(C₁₋₆ alkyl)aminoC₁₋₆ alkyl groups, hydroxy C₁₋₆ alkylamino C₁₋₈ alkyl groups, C₁₋₆alkoxy C₁₋₆ alkylamino C₁₋₆ alkyl groups, bis(C₁₋₆ alkoxy C₁₋₆alkyl)amino C₁₋₆ alkyl groups, (hydroxy C₁₋₆ alkyl)(C₁₋₆ alkoxy C₁₋₆alkyl)amino C₁₋₆ alkyl groups, C₂₋₆ alkanoylamino C₁₋₆ alkyl groups,di(C₂₋₆ alkanoyl)amino C₁₋₆ alkyl groups, carboxyamino C₁₋₆ alkylgroups, di(C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl)amino C₁₋₆ alkyl groups,C₁₋₆ alkoxycarbonylamino C₁₋₆ alkyl groups, di(C₁₋₆ alkoxycarbonyl)aminoC₁₋₆ alkyl groups, carbamoylamino C₁₋₆ alkyl groups, N—C₁₋₆alkylcarbamoylamino C₁₋₆ alkyl groups, N,N-di(C₁₋₆ alkyl)carbamoylaminoC₁₋₆ alkyl groups, aminosulfonylamino C₁₋₆ alkyl groups, N—C₁₋₆alkylsulfonylamino C₁₋₆ alkyl groups, di(C₁₋₆ alkyl)aminosulfonylaminoC₁₋₆ alkyl groups, C₆₋₁₀ aromatic hydrocarbon-sulfonylamino-C₁₋₆alkanoylamino C₁₋₆ alkyl groups, amino C₁₋₆ alkylcarbonylamino C₁₋₆alkyl groups, N—C₁₋₆ alkylamino C₁₋₆ alkylcarbonylamino C₁₋₆ alkylgroups, N,N-di(C₁₋₆ alkyl)amino C₁₋₆ alkylcarbonylamino C₁₋₆ alkylgroups, heterocycle-C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl groups,heterocycle-C₂₋₆ alkenylcarbonylamino C₁₋₆ alkyl groups, C₆₋₁₀ aromatichydrocarbon-alkenylcarbonylamino C₁₋₆ alkyl groups, C₆₋₁₀ aromatichydrocarbon-carbonylamino C₁₋₆ alkyl groups, C₆₋₁₀ aromatichydrocarbon-thiocarbonylamino C₁₋₆ alkyl groups,heterocycle-carbonylamino C₁₋₆ alkyl groups, C₁₋₆ alkoxyoxalylamino C₁₋₆alkyl groups, (C₆₋₁₀ aromatic hydrocarbon-sulfonyl)(C₁₋₆ alkyl)aminoC₁₋₆ alkyl groups, C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl groups, C₁₋₆alkylsulfonylamino C₁₋₆ alkyl groups, carbamoyloxy C₁₋₆ alkyl groups,N—C₁₋₆ alkylcarbamoyloxy C₁₋₆ alkyl groups, N,N-di(C₁₋₆alkyl)carbamoyloxy C₁₋₆ alkyl groups, C₆₋₁₀ aromatic hydrocarbon-C₁₋₆alkylcarbamoyloxy C₁₋₆ alkyl groups, C₁₋₆ alkoxycarbonyloxy-C₁₋₆ alkylgroups, C₆₋₁₀ aromatic hydrocarbon-oxycarbonyloxy C₁₋₆ alkyl groups,heterocyclic carbonylhydrazonomethyl groups, C₆₋₁₀ aromatichydrocarbon-carbonylhydrazonomethyl groups, C₂₋₆ alkenyl groups,carboxy-C₂₋₆ alkenyl groups, C₁₋₆ alkoxycarbonyl-C₂₋₆ alkenyl groups,carbamoyl C₂₋₆ alkenyl groups, heterocycle-alkenyl groups, formyl group,carboxyl group, heterocycle-carbonyl groups, C₆₋₁₀ aromatichydrocarbon-carbonyl groups, C₁₋₆ alkoxycarbonyl groups, carbamoylgroup, N—C₁₋₆ alkylcarbamoyl groups, N,N-di(C₁₋₆ alkyl)carbamoyl groups,C₃₋₈ cycloalkyl-C₁₋₆ alkylcarbamoyl groups, C₁₋₆ alkylthio C₁₋₆alkylcarbamoyl groups, C₁₋₆ alkylsulfinyl C₁₋₆ alkylcarbamoyl groups,C₁₋₆ alkylsulfonyl C₁₋₆ alkylcarbamoyl groups, hydroxyaminocarbonylgroup, C₁₋₆ alkoxycarbamoyl groups, hydroxy C₁₋₆ alkylcarbamoyl groups,C₁₋₆ alkoxy C₁₋₆ alkylcarbamoyl groups, amino C₁₋₆ alkylcarbamoylgroups, amino C₁₋₆ alkylthiocarbamoyl groups, hydroxy C₁₋₆alkylcarbamoyl groups, C₁₋₆ alkoxycarbonyl C₁₋₆ alkylcarbamoyl groups,C₁₋₆ alkoxycarbonylamino C₁₋₆ alkylcarbamoyl groups, C₁₋₆alkoxycarbonylamino C₁₋₆ alkylthiocarbamoyl groups,heterocycle-carbamoyl groups, heterocycle-C₁₋₆ alkylcarbamoyl groups,C₆₋₁₀ aromatic hydrocarbon-carbamoyl groups, hydrazinocarbonyl group,N—C₁₋₆ alkylhydrazinocarbonyl groups, N′—C₁₋₆ alkylhydrazinocarbonylgroups, N′,N′-di(C₁₋₆ alkyl)hydrazinocarbonyl groups, N,N′-di(C₁₋₆alkyl)hydrazinocarbonyl groups, N,N′,N′-tri(C₁₋₆ alkyl)hydrazinocarbonylgroups, N′-(heterocycle-carbonyl)-hydrazinocarbonyl groups, amino group,C₁₋₆ alkoxy C₁₋₆ alkylamino groups, amino C₁₋₆ alkylamino groups, C₁₋₆alkylamino C₁₋₆ alkylamino groups, (C₁₋₆ alkylamino C₁₋₆ alkyl)(C₁₋₆alkyl)amino groups, (C₁₋₆ alkylcarbonylamino C₁₋₆ alkyl)amino groups,(C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl)amino groups, C₁₋₆alkoxycarbonylamino C₁₋₆ alkylamino groups, di(C₁₋₆ alkyl)amino C₁₋₆alkylamino groups, heterocycle-amino C₁₋₆ alkylamino groups, carboxylC₁₋₆ alkylamino groups, (carboxyl C₁₋₆ alkyl)(C₁₋₆ alkyl)amino groups,heterocycle-C₁₋₆ alkylamino groups, (heterocycle-C₁₋₆ alkyl)(C₁₋₆alkyl)amino groups, hydroxy C₁₋₆ alkylamino groups, (hydroxy C₁₋₆alkyl)(C₁₋₆ alkyl)amino groups, C₁₋₆ alkylthio C₁₋₆ alkylamino groups,C₁₋₆ alkylaminocarbonyloxy C₁₋₆ alkylamino groups, (C₁₋₆alkylaminocarbonyloxy C₁₋₆ alkyl)(C₁₋₆ alkyl)amino groups, C₁₋₆alkylsulfinyl C₁₋₆ alkylamino groups, C₁₋₆ alkylsulfonyl C₁₋₆ alkylaminogroups, groups represented by the formula: —N(R¹²)SO₂R¹¹ (wherein, R¹¹represents a C₁₋₆ alkyl group, heterocyclic group, C₁₋₆alkyl-heterocyclic group, heterocycle-C₁₋₆ alkyl group, hydroxy C₁₋₆alkyl group, amino C₁₋₆ alkyl group, C₁₋₆ alkylamino C₁₋₆ alkyl group,di(C₁₋₆ alkyl)amino C₁₋₆ alkyl group, carboxy C₁₋₆ alkyl group,carbamoyl C₁₋₆ alkyl group, trifluoromethyl group, difluoromethyl group,fluoromethyl group, amino group, C₁₋₆ alkylamino group or di(C₁₋₆alkyl)amino group, R¹² represents hydrogen atom, C₁₋₆ alkyl group,hydroxy group or amino group), hydroxy C₁₋₆ alkoxy C₁₋₆ alkylaminogroups, C₆₋₁₀ aromatic hydrocarbon-C₁₋₆ alkylamino groups,heterocycle-carbonylamino groups, C₁₋₆ alkoxycarbonylamino groups,heterocycle-C₁₋₆ alkylcarbonylamino groups, C₆₋₁₀ aromatichydrocarboncarbonylamino groups, heterocycle-amino-groups, hydroxyiminogroup, C₁₋₆ alkoxyimino groups, oxo group, hydroxyimino C₁₋₆ alkylgroups, C₁₋₆ alkoxycarbonyl C₁₋₆ alkylamino groups, (C₂₋₆ alkanoylaminoC₁₋₆ alkyl)amino groups, C₆₋₁₀ aromatic hydrocarbon groups, andheterocyclic groups (in which, the C₆₋₁₀ aromatic hydrocarbon group orheterocycle or heterocyclic group may be substituted with 1 to 3substituents selected from halogen atoms, C₁₋₆ alkyl groups, C₁₋₆ alkoxygroups, C₂₋₆ alkenyl groups, formyl group, C₂₋₆ alkanoyl groups,carboxyl group, carboxyamino C₁₋₆ alkyl groups, C₁₋₆ alkoxycarbonylaminoC₁₋₆ alkyl groups, oxo group, nitro group, cyano group, amidino group,C₂₋₆ alkenyloxy groups, hydroxy group, thioxo group, amino group, C₁₋₆alkylamino groups, di(C₁₋₆ alkyl)amino groups, amino C₁₋₆ alkyl groups,C₁₋₆ alkoxycarbonyl groups, carbamoyl group, C₁₋₆ alkylcarbamoyl groups,di(C₁₋₆ alkyl)carbamoyl groups, thiocarbamoyl group, C₁₋₆alkylthiocarbamoyl groups, di(C₁₋₆ alkyl)thiocarbamoyl groups, C₂₋₆alkanoylamino groups, C₂₋₆ alkanoyl(C₁₋₆ alkyl)amino groups, thio C₂₋₆alkanoylamino groups, thio C₂₋₆ alkanoyl(C₁₋₆ alkyl)amino groups,formylamino group, formyl(C₁₋₆ alkyl)amino groups, thioformylaminogroup, thioformyl(C₁₋₆ alkyl)amino groups, C₂₋₆ alkanoyloxy groups,formyloxy group, mercapto group, C₁₋₆ alkylthio groups, C₁₋₆alkylsulfinyl groups, C₁₋₆ alkylsulfonyl groups, aminosulfonyl group,C₁₋₆ alkylaminosulfonyl groups, di(C₁₋₆ alkyl)aminosulfonyl groups, C₁₋₆alkylsulfonylamino groups, and C₁₋₆ alkylsulfonyl(C₁₋₆ alkyl)aminogroups); an N-oxide or S-oxide thereof; a salt thereof; or a solvatethereof.
 7. A compound according to claim 5, wherein R² represents apyridyl group which may be substituted with 1 to 3 substituents selectedfrom halogen atoms, cyano group, C₁₋₆ alkyl groups, hydroxy group, C₁₋₆alkoxy groups, C₂₋₆ alkenyloxy groups, carboxy C₁₋₆ alkyl groups, C₁₋₆alkoxycarbonyl C₁₋₆ alkyl groups, heterocycle-carbonyl C₁₋₆ alkylgroups, hydroxy C₁₋₆ alkyl groups, C₆₋₁₀ aromatic hydrocarbon-sulfonylC₁₋₆ alkyl groups, N,N-di(C₁₋₆ alkyl)aminosulfonyl C₁₋₆ alkyl groups,heterocycle-C₁₋₆ alkyl groups, C₆₋₁₀ aromatic hydrocarbon-C₁₋₆ alkylgroups, C₆₋₁₀ aromatic hydrocarbon-thio C₁₋₆ alkyl groups, azido-C₁₋₆alkyl groups, amino C₁₋₆ alkyl groups, C₁₋₆ alkylamino C₁₋₆ alkylgroups, di(C₁₋₆ alkyl)amino C₁₋₆ alkyl groups, hydroxy C₁₋₆ alkylaminoC₁₋₆ alkyl groups, C₁₋₆ alkoxy C₁₋₆ alkylamino C₁₋₆ alkyl groups,bis(C₁₋₆ alkoxy C₁₋₆ alkyl)amino C₁₋₆ alkyl groups, (hydroxy C₁₋₆alkyl)(C₁₋₆ alkoxy C₁₋₆ alkyl)amino C₁₋₆ alkyl groups, C₂₋₆alkanoylamino C₁₋₆ alkyl groups, di(C₂₋₆ alkanoyl)amino C₁₋₆ alkylgroups, carboxyamino C₁₋₆ alkyl groups, di(C₁₋₆ alkylcarbonylamino C₁₋₆alkyl)amino C₁₋₆ alkyl groups, C₁₋₆ alkoxycarbonylamino C₁₋₆ alkylgroups, di(C₁₋₆ alkoxycarbonyl)amino C₁₋₆ alkyl groups, carbamoylaminoC₁₋₆ alkyl groups, N—C₁₋₆ alkylcarbamoylamino C₁₋₆ alkyl groups,N,N-di(C₁₋₆ alkyl)carbamoylamino C₁₋₆ alkyl groups, aminosulfonylaminoC₁₋₆ alkyl groups, N—C₁₋₆ alkylsulfonylamino C₁₋₆ alkyl groups, di(C₁₋₆alkyl)aminosulfonylamino C₁₋₆ alkyl groups, C₆₋₁₀ aromatichydrocarbon-sulfonylamino-C₂₋₆ alkanoylamino C₁₋₆ alkyl groups, aminoC₁₋₆ alkylcarbonylamino C₁₋₆ alkyl groups, N—C₁₋₆ alkylamino C₁₋₆alkylcarbonylamino C₁₋₆ alkyl groups, N,N-di(C₁₋₆ alkyl)amino C₁₋₆alkylcarbonylamino C₁₋₆ alkyl groups, heterocycle-C₁₋₆alkylcarbonylamino C₁₋₆ alkyl groups, heterocycle-C₂₋₆alkenylcarbonylamino C₁₋₆ alkyl groups, C₆₋₁₀ aromatic hydrocarbon-C₂₋₆alkenylcarbonylamino C₁₋₆ alkyl groups, C₆₋₁₀ aromatichydrocarbon-carbonylamino C₁₋₆ alkyl groups, C₆₋₁₀ aromatichydrocarbonthiocarbonylamino C₁₋₆ alkyl groups, heterocyclecarbonylaminoC₁₋₆ alkyl groups, C₁₋₆ alkoxyoxalylamino C₁₋₆ alkyl groups, (C₆₋₁₀aromatic hydrocarbon-sulfonyl)(C₁₋₅ alkyl)amino C₁₋₆ alkyl groups, C₁₋₆alkylsulfonylamino C₁₋₆ alkyl groups, C₁₋₆ alkylsulfonylamino C₁₋₆ alkylgroups, carbamoyloxy C₁₋₆ alkyl groups, N—C₁₋₆ alkylcarbamoyloxy C₁₋₆alkyl groups, N,N-di(C₁₋₆ alkyl)carbamoyloxy C₁₋₆ alkyl groups, C₆₋₁₀aromatic hydrocarbon-C₁₋₆ alkylcarbamoyloxy C₁₋₆ alkyl groups, C₁₋₆alkoxycarbonyloxy-C₁₋₆ alkyl groups, C₆₋₁₀ aromatichydrocarbon-oxycarbonyloxy C₁₋₆ alkyl groups, heterocyclecarbonylhydrazonomethyl groups, C₆₋₁₀ aromatic hydrocarboncarbonylhydrazonomethyl groups, C₂₋₆ alkenyl groups, carboxy-C₂₋₅alkenyl groups, C₁₋₆ alkoxycarbonyl-C₂₋₆ alkenyl groups, carbamoyl C₂₋₆alkenyl groups, heterocycleC₂₋₆ alkenyl groups, formyl group, carboxylgroup, heterocycle-carbonyl groups, C₆₋₁₀ aromatic hydrocarboncarbonylgroups, C₁₋₆ alkoxycarbonyl groups, carbamoyl group, N—C₁₋₆alkylcarbamoyl groups, N,N-di(C₁₋₆ alkyl)carbamoyl groups, C₃₋₈cycloalkyl-C₁₋₆ alkylcarbamoyl groups, C₁₋₆ alkylthio C₁₋₆alkylcarbamoyl groups, C₁₋₆ alkylsulfinyl C₁₋₆ alkylcarbamoyl groups,C₁₋₆ alkylsulfonyl C₁₋₆ alkylcarbamoyl groups, hydroxyaminocarbonylgroup, C₁₋₆ alkoxycarbamoyl groups, hydroxy C₁₋₆ alkylcarbamoyl groups,C₁₋₆ alkoxy C₁₋₆ alkylcarbamoyl groups, amino C₁₋₆ alkylcarbamoylgroups, amino C₁₋₆ alkylthiocarbamoyl groups, hydroxy C₁₋₆alkylcarbamoyl groups, C₁₋₆ alkoxycarbonyl C₁₋₆ alkylcarbamoyl groups,C₁₋₆ alkoxycarbonylamino C₁₋₆ alkylcarbamoyl groups, C₁₋₆alkoxycarbonylamino C₁₋₆ alkylthiocarbamoyl groups,heterocycle-carbamoyl groups, heterocycle-C₁₋₆ alkylcarbamoyl groups,C₆₋₁₀ aromatic hydrocarbon-carbamoyl groups, hydrazinocarbonyl groups,N—C₁₋₆ alkylhydrazinocarbonyl groups, N′—C₁₋₆ alkylhydrazinocarbonylgroups, N′,N′-di(C₁₋₆ alkyl)hydrazinocarbonyl groups, N,N′-di(C₁₋₆alkyl)hydrazinocarbonyl groups, N,N′,N′-tri(C₁₋₆ alkyl)hydrazinocarbonylgroups, N′-(heterocycle-carbonyl)-hydrazinocarbonyl groups, amino group,C₁₋₆ alkoxy C₁₋₆ alkylamino groups, amino C₁₋₆ alkylamino groups, (C₁₋₆alkylamino C₁₋₆ alkylamino groups, (C₁₋₆ alkylamino C₁₋₆ alkyl)(C₁₋₆alkyl)amino groups, C₁₋₆ alkoxycarbonylamino C₁₋₆ alkylamino groups,di(C₁₋₆ alkyl)amino C₁₋₆ alkylamino groups, heterocycle-amino C₁₋₆alkylamino groups, carboxyl C₁₋₆ alkylamino groups, (carboxyl C₁₋₆alkyl)(C₁₋₆ alkyl)amino groups, heterocycle-C₁₋₆ alkylamino groups,(heterocycle-C₁₋₆ alkyl)(C₁₋₆ alkyl)amino groups, hydroxy C₁₋₆alkylamino groups, (hydroxy C₁₋₆ alkyl)(C₁₋₆ alkyl)amino groups, C₁₋₆alkylthio C₁₋₆ alkylamino groups, C₁₋₆ alkylaminocarbonyloxy C₁₋₆alkylamino groups, (C₁₋₆ alkylaminocarbonyloxy C₁₋₆ alkyl)(C₁₋₆alkyl)amino groups, C₁₋₆ alkylsulfinyl C₁₋₆ alkylamino groups, C₁₋₆alkylsulfonyl C₁₋₆ alkylamino groups, groups represented by the formula:—N(R¹²)SO₂R¹¹ (wherein, R¹¹ represents a C₁₋₆ alkyl group, heterocyclicgroup, C₁₋₆ alkyl-heterocyclic group, heterocycle-C₁₋₆ alkyl group,hydroxy C₁₋₆ alkyl group, amino C₁₋₆ alkyl group, C₁₋₆ alkylamino C₁₋₆alkyl group, di(C₁₋₆ alkyl)amino C₁₋₆ alkyl group, carboxy C₁₋₆ alkylgroup, carbamoyl C₁₋₆ alkyl group, trifluoromethyl group, difluoromethylgroup, fluoromethyl group, amino group, C₁₋₆ alkylamino group or di(C₁₋₆alkyl)amino group, R¹² represents a hydrogen atom, C₁₋₆ alkyl group,hydroxy group or amino group), hydroxy C₁₋₆ alkoxy C₁₋₆ alkylaminogroups, C₆₋₁₀ aromatic hydrocarbon-C₁₋₆ alkylamino groups,heterocycle-carbonylamino groups, C₁₋₆ alkoxycarbonylamino groups,heterocycle-C₁₋₆ alkylcarbonylamino groups, C₆₋₁₀ aromatichydrocarboncarbonylamino groups, heterocycle-amino groups, hydroxyiminogroup, C₁₋₆ alkoxyimino groups, oxo group, hydroxyimino C₁₋₆ alkylgroups, C₁₋₆ alkoxycarbonyl C₁₋₆ alkylamino groups, (C₂₋₆ alkanoylaminoC₁₋₆ alkyl)amino groups, C₆₋₁₀ aromatic hydrocarbon groups, andheterocyclic groups (in which, the C₆₋₁₀ aromatic hydrocarbon group orheterocyclic group may be substituted with 1 to 3 substituents selectedfrom halogen atoms, C₁₋₆ alkyl groups, C₁₋₆ alkoxy groups, C₂₋₆ alkenylgroups, formyl group, C₂₋₆ alkanoyl groups, carboxyl group, carboxyaminoC₁₋₆ alkyl groups, C₁₋₆ alkoxycarbonylamino C₁₋₆ alkyl groups, oxogroup, nitro group, cyano group, amidino group, C₂₋₆ alkenyloxy groups,hydroxy group, thioxo group, amino group, C₁₋₆ alkylamino groups,di(C₁₋₆alkyl)amino groups, amino C₁₋₆ alkyl groups, C₁₋₆ alkoxycarbonylgroups, carbamoyl group, C₁₋₆ alkylcarbamoyl groups, di(C₁₋₆alkyl)carbamoyl groups, thiocarbamoyl group, C₁₋₆ alkylthiocarbamoylgroups, di(C₁₋₆ alkyl)thiocarbamoyl groups, C₂₋₆ alkanoylamino groups,C₂₋₆ alkanoyl(C₁₋₆ alkyl)amino groups, thio C₂₋₆ alkanoylamino groups,thio C₂₋₆ alkanoyl(C₁₋₆ alkyl)amino groups, formylamino group,formyl(C₁₋₆ alkyl)amino groups, thioformylamino group, thioformyl(C₁₋₆alkyl)amino groups, C₂₋₆ alkanoyloxy groups, formyloxy group, mercaptogroup, C₁₋₆ alkylthio groups, C₁₋₆ alkylsulfinyl groups, C₁₋₆alkylsulfonyl groups, aminosulfonyl group, C₁₋₆ alkylaminosulfonylgroups, di(C₁₋₆ alkyl)aminosulfonyl groups, C₁₋₆ alkylsulfonylaminogroups, and C₁₋₆ alkylsulfonyl(C₁₋₆ alkyl)amino groups; an N-oxide orS-oxide thereof; a salt thereof; or a solvate thereof.
 8. A compoundaccording to claim 5, wherein R² represents a group represented by thefollowing formula:

(wherein, R¹⁰ represents a hydrogen atom, C₁₋₆ alkyl group, hydroxy C₁₋₆alkyl group, C₁₋₆ alkylsulfinyl C₁₋₆ alkyl group, C₁₋₆ alkylsulfonylC₁₋₆ alkyl group, carboxy C₁₋₆ alkyl group, heterocycle-C₁₋₆ alkylgroup, or a group represented by the formula: —SO₂—R¹¹ (in which, R¹¹represents a C₁₋₆ alkyl, heterocyclic, C₁₋₆ alkyl-heterocyclic,heterocycle-C₁₋₆ alkyl, hydroxy C₁₋₆ alkyl, amino C₁₋₆ alkyl, C₁₋₆alkylamino C₁₋₆ alkyl, di(C₁₋₆ alkyl)amino C₁₋₆ alkyl, carboxy C₁₋₆alkyl, carbamoyl C₁₋₆ alkyl, trifluoromethyl, difluoromethyl,fluoromethyl, amino, C₁₋₆ alkylamino or di(C₁₋₆ alkyl)amino), R¹²represents a hydrogen atom, C₁₋₆ alkyl group, hydroxy group, or aminogroup, or R¹¹ and R¹² may, taken together with a sulfur atom to whichR¹¹ is attached and a nitrogen atom to which R¹² is attached, form a 5-or 6-membered aliphatic heterocycle, and R¹³ represents a C₁₋₆ alkylgroup, halogen atom or cyano group); an N-oxide or S oxide thereof; asalt thereof; or a solvate thereof.
 9. A compound according to claim 5,wherein R² represents a group represented by the following formula:

(wherein, R¹⁰ represents a group represented by the formula: —SO₂—R¹¹(in which, R¹¹ represents a C₁₋₆ alkyl, heterocyclic, C₁₋₆alkyl-heterocyclic, heterocycle-C₁₋₆ alkyl, hydroxy C₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₁₋₆ alkylamino C₁₋₆ alkyl, di(C₁₋₆ alkyl)amino C₁₋₆ alkyl,carboxy C₁₋₆ alkyl, carbamoyl C₁₋₆ alkyl, trifluoromethyl,difluoromethyl, fluoromethyl, amino, C₁₋₆ alkylamino or di(C₁₋₆alkyl)amino), R¹² represents a hydrogen atom, C₁₋₆ alkyl group, hydroxygroup or amino group, or R¹¹ and R¹² may, taken together with a sulfuratom to which R¹¹ is attached and a nitrogen atom to which R¹² isattached, form a 5- or 6-membered aliphatic heterocycle, and R¹³represents a C₁₋₆ alkyl group, halogen atom or cyano group); an N-oxideor S-oxide thereof; a salt thereof; or a solvate thereof.
 10. A compoundaccording to claim 5, wherein R² represents a compound represented bythe formula:

(wherein, R¹³ represents a C₁₋₆ alkyl group, halogen atom or cyanogroup, and n stands for an integer of from 0 to 6); an N-oxide orS-oxide thereof; a salt thereof; or a solvate thereof
 11. A compoundaccording to claim 1, wherein R¹ represents a 2,5-difluorophenyl or2-fluoro-5-cyanophenyl group, R³ represents a 4-chlorophenyl,4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl,3-fluoro-4-chlorophenyl, 4-trifluoromethylphenyl, 5-chloro-2-thienyl,5-chloro-2-pyridyl, 6-chloro-3-pyridyl, or 6-trifluoromethyl-3-pyridylgroup; R² represents a group represented by the following formula:

(wherein, R¹⁰ represents a hydrogen atom, C₁₋₆ alkyl group, hydroxy C₁₋₆alkyl group, C₁₋₆ alkylsulfinyl C₁₋₆ alkyl group, C₁₋₆ alkylsulfonylC₁₋₆ alkyl group, carboxy C₁₋₆ alkyl group, heterocycle-C₁₋₆ alkylgroup, or a group represented by the formula: —SO₂—R¹¹ (in which, R¹¹represents a C₁₋₆ alkyl, heterocyclic, C₁₋₆ alkyl-heterocyclic,heterocycle-C₁₋₆ alkyl, hydroxy C₁₋₆ alkyl, amino C₁₋₆ alkyl, C₁₋₆alkylamino C₁₋₆ alkyl, di(C₁₋₆ alkyl)amino C₁₋₆ alkyl, carboxy C₁₋₆alkyl, carbamoyl C₁₋₆ alkyl, trifluoromethyl, difluoromethyl,fluoromethyl, amino, C₁₋₆ alkylamino, or di(C₁₋₆ alkyl)amino), R¹²represents a hydrogen atom, C₁₋₆ alkyl group, hydroxy group, or aminogroup, or R¹¹ and R¹² may, taken together with a sulfur atom to whichR¹¹ is attached and a nitrogen atom to which R¹² is attached, form a 5-or 6-membered aliphatic heterocycle, and R¹³ represents a C₁₋₆ alkylgroup, halogen atom or cyano group); an N-oxide or S-oxide thereof; asalt thereof; or a solvate thereof.
 12. A compound according to claim 1,wherein R¹ represents a 2,5-difluorophenyl or 2-fluoro-5-cyanophenylgroup, R³ represents a 4-chlorophenyl, 4-fluorophenyl,2,4-difluorophenyl, 3,4-difluorophenyl, 3-fluoro-4-chlorophenyl,4-trifluoromethylphenyl, 5-chloro-2-thienyl, 5-chloro-2-pyridyl,6-chloro-3-pyridyl or 6-trifluoromethyl-3-pyridyl group; R² represents agroup represented by the following formula:

(wherein, R¹⁰ represents a group represented by the formula: —SO₂—R¹¹(in which, R¹¹ represents a C₁₋₆ alkyl, heterocyclic, C₁₋₆alkyl-heterocyclic, heterocycle-C₁₋₆ alkyl, hydroxy C₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₁₋₆ alkylamino C₁₋₆ alkyl, di(C₁₋₆ alkyl)amino C₁₋₆ alkyl,trifluoromethyl, difluoromethyl, fluoromethyl, amino, C₁₋₆ alkylamino ordi(C₁₋₆ alkyl)amino), R represents a hydrogen atom, C₁₋₆ alkyl group,hydroxy group or amino group, or R¹¹ and R¹² may, taken together with asulfur atom to which R¹¹ is attached and a nitrogen atom to which R¹² isattached, form a 5- or 6-membered aliphatic heterocycle, and R¹³represents a C₁₋₆ alkyl group, halogen atom or cyano group); an N-oxideor S-oxide thereof; a salt thereof; or a solvate thereof.
 13. A compoundaccording to claim 1, wherein R¹ represents a 2,5-difluorophenyl or2-fluoro-5-cyanophenyl group, R³ represents a 4-chlorophenyl,4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl,3-fluoro-4-chlorophenyl, 4-trifluoromethylphenyl, 5-chloro-2-thienyl,5-chloro-2-pyridyl, 6-chloro-3-pyridyl, or 6-trifluoromethyl-3-pyridylgroup; R² represents a group represented by the following formula:

(wherein, R¹³ represents a C₁₋₆ alkyl group, halogen atom or cyano groupand n stands for an integer of from 0 to 6); an N-oxide or S-oxidethereof; a salt thereof; or a solvate thereof.
 14. A medicamentcomprising, as an effective ingredient, a compound as claimed in any oneof claims 1 to 13; an N-oxide or S-oxide thereof; a salt thereof; or asolvate thereof.
 15. A medicament according to claim 14, which is usedfor prevention or treatment of a disease resulting from abnormalproduction or secretion of β-amyloid protein.
 16. A medicament accordingto claim 15, wherein the disease resulting from abnormal production orsecretion of β amyloid protein is Alzheimer disease or Down syndrome.17. A pharmaceutical composition comprising a compound as claimed in anyone of claims 1 to 13, an N-oxide or S oxide thereof, a salt thereof ora solvate thereof and a pharmaceutically acceptable carrier.
 18. Use ofa compound as claimed in any one of claims 1 to 13, an N-oxide or Soxide thereof, a salt thereof or a solvate thereof for the preparationof a medicament.
 19. Use according to claim 18, wherein the medicamentis a preventive or remedy for a disease resulting from abnormalproduction or secretion of β-amyloid protein.
 20. Use according to claim19, wherein the disease resulting from abnormal production or secretionof β amyloid protein is Alzheimer disease or Down syndrome.
 21. A methodof treating a disease resulting from abnormal production or secretion ofβ-amyloid protein, which comprises administering an effective amount ofa compound as claimed in any one of claims 1 to 13, an N-oxide orS-oxide thereof, a salt thereof, or a solvate thereof.
 22. A treatingmethod according to claim 21, wherein the disease resulting fromabnormal production or secretion of β amyloid protein is Alzheimerdisease or Down syndrome.